Alzheimer's Disease

Cognitively normal individuals with AD parents may be at risk for developing aging-related cortical thinning patterns characteristic of AD

by Derin Cobia

Biomarkers for diagnosing Alzheimer's Disease and other dementia.

by Andy Kahn

lzheimer's disease (AD), the most common cause of dementia in older individuals, is a debilitating neurodegenerative disease for which there is no definitive cure as of now. It destroys the neurons in parts of the brain, chiefly the hippocampus, which is a region involved in coding memories. Alzheimer's disease gives rise to an irreversible progressive loss of cognitive functions and of functional autonomy. The earliest signs of AD may be mistaken for simple forgetfulness, but in those who are eventually diagnosed with the disease, these initial signs inexorably progress to more severe symptoms of mental deterioration. While the time it takes for AD to develop will vary from person to person, advanced signs include severe memory impairment, confusion, language disturbances, personality and behavior changes, and impaired judgement. Persons with AD may become non-communicative and hostile. As the disease ends its course in profound dementia, patients are unable to care for themselves and often require institutionalization or professional care in the home setting. While some patients may live for years after being diagnosed with AD, the average life expectancy after diagnosis is eight years.

Methods and compositions relating to Alzheimer's disease are done by analyzing the proteins that are differentially... more Methods and compositions relating to Alzheimer's disease are done by analyzing the proteins that are differentially expressed in the brain in the Alzheimer's disease state. These are very much different from the proteins in normal brain.

Dementia is one of the major public health problems of the geriatric population. But off late it seems to affecting even those in their thirties. Increasing numbers of patients with dementia are imposing a major financial burden on health systems around the world. More than half of the patients with dementia have Alzheimer's disease (AD). The prevalence and incidence of AD have been shown to increase exponentially. The prevalence for AD in Europe is 0.5% for ages 60-69 years, 4.2% for ages 70-79 years, and 13.8% for ages 80-89 years. The survival time after the onset of AD is approximately from 3 to 10 years. Death occurs as the brain cells are starved of the energy and nutrients.

Alzheimer's disease (AD), the most common cause of dementia in older individuals, is a debilitating neurodegenerative disease for which there is no definitive cure as of now. It destroys the neurons in parts of the brain, chiefly the hippocampus, which is a region involved in coding memories. Alzheimer's disease gives rise to an irreversible progressive loss of cognitive functions and of functional autonomy. The earliest signs of AD may be mistaken for simple forgetfulness, but in those who are eventually diagnosed with the disease, these initial signs inexorably progress to more severe symptoms of mental deterioration. While the time it takes for AD to develop will vary from person to person, advanced signs include severe memory impairment, confusion, language disturbances, personality and behavior changes, and impaired judgement. Persons with AD may become non-communicative and hostile. As the disease ends its course in profound dementia, patients are unable to care for themselves and often require institutionalization or professional care in the home setting. While some patients may live for years after being diagnosed with AD, the average life expectancy after diagnosis is eight years.

In the past, AD could only be definitively diagnosed by brain biopsy or upon autopsy after a patient died. These methods, which demonstrate the presence of the characteristic plaque and tangle lesions in the brain, are still considered the gold standard for the pathological diagnoses of AD. However, in the clinical setting brain biopsy is rarely performed and diagnosis depends on a battery of neurological, psychometric and biochemical tests, including the measurement of biochemical markers such as the ApoE and tau proteins or the beta-amyloid peptide in cerebrospinal fluid and blood.

Biomarkers may possibly possess the key in the next step for diagnosing AD and other dementia. A biological marker that fulfils the requirements for the diagnostic test for AD would have several advantages. An ideal biological marker would be one that identifies AD cases at a very early stage of the disease, before there is degeneration observed in the brain imaging and neuropathological tests. A biomarker could be the first indicator for starting treatment as early as possible, and also very valuable in screening the effectiveness of new therapies, particularly those that are focused on preventing the development of neuropathological changes. A biological marker would also be useful in the follow-up of the development of the disease.

Imagerie fonctionnelle de la mémoire aux stades précoces de la maladie d'Alzheimer : dysfonctionnements et mécanismes compensatoires (Tableau)

by Alexandre Bejanin

pH-dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid-beta peptide

by sebastian wärmländer

N‐terminal engineering of amyloid‐β‐binding Affibody molecules yields improved chemical synthesis and higher binding affinity

by sebastian wärmländer

Interaction of synthetic Alzheimer β -protein-derived analogs with aqueous aluminum: A low-field 27 Al NMR investigation

by Sandip Vyas

Stabilization of Secondary Structure of Alzheimer β-Protein by Aluminum(III) Ions and D-Asp Substitutions

by Sandip Vyas

When higher activations reflect lower deactivations, a PET study in Alzheimer’s disease during encoding and retrieval in episodic memory

by Alexandre Bejanin

The aim of the present study was to explore the cerebral substrates of episodic memory disorders in Alzheimer’s... more The aim of the present study was to explore the cerebral substrates of episodic memory disorders in Alzheimer’s disease (AD) and investigate patients’ hyperactivations frequently reported in the functional imaging literature. It remains unclear whether some of these hyperactivations reflect real increased activity or deactivation disturbances in the default mode network (DMN). Using positron emission tomography (15O-H2O), cerebral blood flow was measured in 11 AD patients and 12 healthy elderly controls at rest and during encoding and stem-cued recall of verbal items. Subtractions analyses between the target and control conditions were performed and compared between groups. The average signal was extracted in regions showing hyperactivation in AD patients versus controls in both contrasts. To determine whether hyperactivations occurred in regions that were activated or deactivated during the memory tasks, we compared signal intensities between the target conditions versus rest. Our results showed reduced activation in AD patients compared to controls in several core episodic memory regions, including the medial temporal structures, during both encoding and retrieval. Patients also showed hyperactivations compared to controls in a set of brain areas. Further analyses conducted on the signal extracted in these areas indicated that most of these hyperactivations actually reflected a failure of deactivation. Indeed, whereas almost all of these regions were significantly more activated at rest than during the target conditions in controls, only one region presented a similar pattern of deactivation in patients. Altogether, our findings suggest that hyperactivations in AD must be interpreted with caution and may not systematically reflect increased activity. Although there has been evidence supporting the existence of genuine compensatory mechanisms, dysfunction within the DMN may be responsible for part of the apparent hyperactivations reported in the literature on AD.

Gene by neuroticism interaction and cognitive function among older adults

by Ilan Dar-Nimrod

Dar-Nimrod, I., Chapman, B. P., Robbins, J., Porsteinsson, A., Mapstone, M., & Duberstein, P. R. (in press). Gene by neuroticism interaction and cognitive function among older adults. International Journal of Geriatric Psychiatry.

Imagerie fonctionnelle de la mémoire aux stades précoces de la maladie d'Alzheimer : dysfonctionnements et mécanismes compensatoires

by Alexandre Bejanin

Depuis une quinzaine d’années, de nombreux travaux d’imagerie en activation ont été entrepris dans la maladie... more Depuis une quinzaine d’années, de nombreux travaux d’imagerie en activation ont été entrepris dans la maladie d’Alzheimer et dans la phase prédémentielle de la maladie, c’est-à-dire chez des patients répondant aux critères de troubles cognitifs légers. Ces études permettent d’examiner les substrats cérébraux des troubles cognitifs et d’analyser les signes précurseurs de la maladie. Elles servent également à mettre en évidence les mécanismes de compensation mis en place pour faire face aux anomalies neuropathologiques. Du fait de son atteinte privilégiée et précoce, la mémoire, et notamment la mémoire épisodique, a tout particulièrement suscité l’intérêt des chercheurs. Cet article se propose de synthétiser les principales données, obtenues auprès de patients et concernant la mémoire épisodique, la mémoire sémantique et la mémoire de travail. Il ressort principalement des résultats une altération fonctionnelle de structures clés associées à chacun de ces systèmes mnésiques. Le dysfonctionnement affecte tant les activations que les désactivations induites par des tâches cognitives. En outre, des phénomènes de plasticité cérébrale sont observés. Ils pourraient refléter la mise en place de processus compensatoires. Aux stades prédémentiels, ces mécanismes reposeraient surtout sur des structures attendues compte tenu des processus en jeu. L’entrée dans la démence se traduirait par des modifications compensatoires moins spécifiques et plus distribuées.

High content analysis of γ-secretase activity reveals variable dominance of presenilin mutations linked to familial Alzheimer's disease

by Cristina Florean

gamma-Secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP), Notch and other cellular... more gamma-Secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP), Notch and other cellular substrates and is considered a prime pharmacological target in the development of therapeutics for Alzheimer's disease (AD). We describe here an efficient, new, simple, sensitive and rapid assay to quantify gamma-secretase activity in living cells by flow cytometry using two membrane-bound fluorescent probes, APP-GFP or C99-GFP, as substrates for gamma-secretase. The principle of the assay is based on the fact that the soluble intracellular domain of GFP-tagged APP (AICD-GFP) is released from the membrane into the cytosol following gamma-secretase cleavage. Using this feature, enzymatic activity of gamma-secretase could be deduced from the extent of the membrane retention of the probe observed after plasma membrane permeabilization and washout of the cleaved fraction. By applying two well-known gamma-secretase inhibitors (DAPT and L-685,458), we validated our assay showing that the positional GFP-based probes for gamma-secretase activity behave properly when expressed in different cell lines, providing the basis for the further development of a high-throughput and high content screening for AD targeted drug discovery. Moreover, by co-expression of different familial AD-linked mutated forms of presenilin--the key component of the gamma-secretase complex--in cells devoid of any endogenous gamma-secretase, our method allowed us to evaluate in situ the contribution of different presenilin variants to the modulation of the enzyme.

Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels

by Cristina Florean

Presenilin-1 and -2 (PS1 and PS2) mutations, the major cause of familial Alzheimer's disease (FAD), have been causally... more Presenilin-1 and -2 (PS1 and PS2) mutations, the major cause of familial Alzheimer's disease (FAD), have been causally implicated in the pathogenesis of neuronal cell death through a perturbation of cellular Ca(2+) homeostasis. We have recently shown that, at variance with previous suggestions obtained in cells expressing other FAD-linked PS mutations, PS2-M239I and PS2-T122R cause a reduction and not an increase in cytosolic Ca(2+) rises induced by Ca(2+) release from stores. In this contribution we have used different cell models: human fibroblasts from controls and FAD patients, cell lines (SH-SY5Y, HeLa, HEK293, MEFs) and rat primary neurons expressing a number of PS mutations, e.g. P117L, M146L, L286V, and A246E in PS1 and M239I, T122R, and N141I in PS2. The effects of FAD-linked PS mutations on cytosolic Ca(2+) changes have been monitored either by using fura-2 or recombinant cytosolic aequorin as the probe. Independently of the cell model or the employed probe, the cytosolic Ca(2+) increases, caused by agonist stimulation or full store depletion by drug treatment, were reduced or unchanged in cells expressing the PS mutations. Using aequorins, targeted to the endoplasmic reticulum or the Golgi apparatus, we here show that FAD-linked PS mutants lower the Ca(2+) content of intracellular stores. The phenomenon was most prominent in cells expressing PS2 mutants, and was observed also in cells expressing the non-pathogenic, "loss-of-function" PS2-D366A mutation. Taken as a whole, our findings, while confirming the capability of presenilins to modify Ca(2+) homeostasis, suggest a re-evaluation of the "Ca(2+) overload" hypothesis in AD and a new working hypothesis is presented.

Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake

by Cristina Florean

We have previously shown that familial Alzheimer's disease mutants of presenilin-2 (PS2) and, to a lesser extent, of... more We have previously shown that familial Alzheimer's disease mutants of presenilin-2 (PS2) and, to a lesser extent, of presenilin-1 (PS1) lower the Ca(2+) concentration of intracellular stores. We here examined the mechanism by which wild-type and mutant PS2 affect store Ca(2+) handling. By using HeLa, SH-SY5Y and MEFs as model cells, and recombinant aequorins as Ca(2+) probes, we show evidence that transient expression of either wild-type or mutant PS2 increases the passive Ca(2+) leakage: both ryanodine- and IP(3)-receptors contribute to Ca(2+) exit out of the ER, whereas the ribosome translocon complex is not involved. In SH-SY5Y cells and MEFs, wild-type and mutant PS2 potently reduce the uptake of Ca(2+) inside the stores, an effect that can be counteracted by over-expression of SERCA-2B. On this line, in wild-type MEFs, lowering the endogenous level of PS2 by RNA interference, increases the Ca(2+)-loading capability of intracellular stores. Furthermore, we show that in PS double knockout MEFs, reduction of Ca(2+) stores is mimicked by the expression of PS2-D366A, a loss-of-function mutant, uncleaved because also devoid of presenilinase activity but not by co-expression of the two catalytic active fragments of PS2. In summary, both physiological and increased levels of wild-type and mutant PS2 reduce the Ca(2+) uptake by intracellular stores. To exert this newly described function, PS2 needs to be in its full-length form, even if it can subsequently be cleaved.

Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake

by Cristina Florean

We have previously shown that familial Alzheimer's disease mutants of presenilin-2 (PS2) and, to a lesser extent, of... more We have previously shown that familial Alzheimer's disease mutants of presenilin-2 (PS2) and, to a lesser extent, of presenilin-1 (PS1) lower the Ca(2+) concentration of intracellular stores. We here examined the mechanism by which wild-type and mutant PS2 affect store Ca(2+) handling. By using HeLa, SH-SY5Y and MEFs as model cells, and recombinant aequorins as Ca(2+) probes, we show evidence that transient expression of either wild-type or mutant PS2 increases the passive Ca(2+) leakage: both ryanodine- and IP(3)-receptors contribute to Ca(2+) exit out of the ER, whereas the ribosome translocon complex is not involved. In SH-SY5Y cells and MEFs, wild-type and mutant PS2 potently reduce the uptake of Ca(2+) inside the stores, an effect that can be counteracted by over-expression of SERCA-2B. On this line, in wild-type MEFs, lowering the endogenous level of PS2 by RNA interference, increases the Ca(2+)-loading capability of intracellular stores. Furthermore, we show that in PS double knockout MEFs, reduction of Ca(2+) stores is mimicked by the expression of PS2-D366A, a loss-of-function mutant, uncleaved because also devoid of presenilinase activity but not by co-expression of the two catalytic active fragments of PS2. In summary, both physiological and increased levels of wild-type and mutant PS2 reduce the Ca(2+) uptake by intracellular stores. To exert this newly described function, PS2 needs to be in its full-length form, even if it can subsequently be cleaved.

The Lives of Our Mad Mothers: Ageing and Contemporary Performance

by Anna Harpin

Published in Women and Performance: A Journal of Feminist Theory, 2012

ADRD National Meeting Report 2010

by Kristen Jacklin

Vilhauer, R.P. (2012). What Was Left. Yale Journal for Humanities in Medicine. February 2012.

by Ruvanee Vilhauer

Yale Journal for Humanities in Medicine
http://yjhm.yale.edu/essays/rvilhauer20120216.htm

Semantic knowledge in MCI and Alzheimer’s disease: The French version of the New Words Interview

by Nathalie Bedoin

Published in
Revue Neurologique 165 (2009) 45 - 48

Introduction : un certain nombre de travaux récents suggère
d’explorer la mémoire sémantique dans la Maladie... more Introduction : un certain nombre de travaux récents suggère
d’explorer la mémoire sémantique dans la Maladie d’Alzheimer
(MA) qui serait altérée précocement et dès le stade des
troubles cognitifs légers (MCI).
Matériel et méthodes : nous proposons le Questionnaire des
Mots Nouveaux (QMN) qui explore la connaissance de 22 nouveaux
mots de la langue française apparus dans le dictionnaire
entre 1996 et 1997, et entre 2006 et 2007. Les mots des deux
périodes sont appariés selon divers critères de surface. Le QMN
comporte trois types d’épreuves : une évocation libre, un choix
multiple de définitions (QCM), une mise en contexte du mot.
Concernant l’évocation libre, la qualité des réponses est évaluée
et l’on distingue les définitions du concept, les exemples en
situation et les définitions par l’usage. Nous avons évalué 12
sujets MCI, 12 patients MA et 72 personnes normales, dont 12
étaient appariées aux patients MCI et MA en âge et en niveau
d’éducation.
Résultats : Du point de vue quantitatif, les performances des
patients MCI et MA sont significativement inférieures à celles
des témoins pour les trois types d’épreuves, et ce pour les mots
des deux périodes. De plus, dès le stade du MCI, les patients se
caractérisent par un échec au QCM par rapport à l’épreuve de
mise en contexte et par des difficultés à élaborer des définitions
conceptuelles, ce qui corrobore l’hypothèse de troubles
sémantiques bien antérieurs au diagnostic de MA. Les patients
MA se distinguent des MCI par une détérioration accrue des
performances dans toutes les épreuves, en particulier le QCM,
signe d’une fragilisation des traits sémantiques stockés. Du
point de vue qualitatif, leurs définitions conceptuelles se
raréfient encore plus que pour les sujets MCI et la stratégie de
compensation par l’évocation d’exemples n’est plus efficace
dans la MA.
Conclusion : les apprentissages récents en mémoire sémantique
sont fragilisés dans le MCI et la MA ce qui semble
confirmer l’atteinte précoce de ce système.

Why Digitise Historical Television?

by John Ellis

Proposing new uses for archive TV now it's online, including use with dementia/Alzheimer's sufferers. A new article in a new online journal from www.euscreen.eu

Digitisation of historic TV material is driven by the widespread perception that archival material should be made... more Digitisation of historic TV material is driven by the widespread perception that archival material should be made available to diverse users. Yet digitisation alters the material, taking away any lingering sense of presence. Digitisation and online access, however, offer startling new possibilities. The article offers three: use of material in language teaching and learning; use in dementia therapy; and applications as data in medical research. All depend on ordinary TV for their effectivity.

Identità personale e testamento biologico: il caso della malattia di Alzheimer

by Matteo Galletti

published in "Bioetica. Rivista interdisciplinare", XII (2004), 3, pp. 400-412

The paper examines a criticism to the moral authority of living will in case of Alzheimer disease: there's a... more The paper examines a criticism to the moral authority of living will in case of Alzheimer disease: there's a disruption of identity over time between the person who signes the directive and the person who shall fall ill. Four thesis about personal identity (psychological identity, bodily identity, biological identity, and moral identity) are discussed in order to give some moral value to living wills.