Journal of Alzheimer's Disease - Volume 29, issue 1

Authors: Passmore, Michael J. | Ho, Anita | Gallagher, Romayne

Article Type: Review Article

Abstract: The assessment and management of behavioral and psychological symptoms of dementia (BPSD) in moderate to severe Alzheimer's disease (AD) can be challenging, and ethical dilemmas often arise. Clinicians often perceive a disconnect between evidence-based guidelines and the challenges of treating BPSD in moderate to severe AD. Reconciliation of salient ethical issues can help bridge this disconnect. In view of the fact that AD is a progressive and ultimately fatal disease, and given that there are often competing considerations when managing BPSD in moderate to severe AD, we propose a palliative care approach that prioritizes the recognition of personhood and the …preservation of dignity. We present case illustrations, discuss the concepts of dignity and personhood during palliative care in AD, and encourage the use of the bioethical grid in navigating complex clinical challenges. Show more

Keywords: Aggression, antipsychotic agents, dementia, ethics, psychomotor agitation, psychotic disorders

DOI: 10.3233/JAD-2012-111424

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 1-13, 2012

Authors: Guerchet, Maëlenn | Mouanga, Alain M. | M'belesso, Pascal | Tabo, André | Bandzouzi, Bébène | Paraïso, Moussiliou N. | Houinato, Dismand S. | Cowppli-Bony, Pascale | Nubukpo, Philippe | Aboyans, Victor | Clément, Jean-Pierre | Dartigues, Jean-François | Preux, Pierre-Marie

Article Type: Research Article

Abstract: Risk factors for dementia in American and European countries have been well investigated. However, little research has been carried out in sub-Saharan Africa, where life events as well as environmental, socio-economic, and modifiable risk factors (i.e., cardiovascular risk factors) may differ. Two cross-sectional surveys were conducted in representative samples of the older general population living in Bangui (Central African Republic) and Brazzaville (Congo). Dementia was defined according to the DSM-IV criteria. Multivariate regression analyses were performed in order to identify independent factors associated with dementia. Among the 977 elderly Africans included in this analysis, 75 (7.6%) were diagnosed as having …dementia. Increasing age, female gender, hypertension, a body mass index <18.5 kg/m2 , depressive symptoms, and the lack of a primary education were significantly associated with dementia. Among life events, the death of one parent during childhood and recently having moved house were also associated with dementia. Beyond the usual risk factors for dementia, this study highlights the role of stressful events in low-income countries. Factors associated with dementia in African countries seem different from established factors in high-income countries and require further investigation. Show more

Keywords: Africa, Alzheimer's disease, dementia, epidemiology, risk factors

DOI: 10.3233/JAD-2011-111364

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 15-24, 2012

Authors: Baglio, Francesca | Castelli, Ilaria | Alberoni, Margherita | Blasi, Valeria | Griffanti, Ludovica | Falini, Andrea | Nemni, Raffello | Marchetti, Antonella

Article Type: Research Article

Abstract: Theory of Mind (ToM) undergoes changes at the behavioral level in pathological aging (Alzheimer's disease (AD)) and at the neural level in physiological aging. The aim was to determine if there are changes in ToM in the behavioral and neural domains in old subjects with high risk of switching from successful to unsuccessful neurocognitive aging. Patients with amnestic mild cognitive impairment (aMCI) syndrome were studied, since aMCI was proposed to fill the gap between normal aging and dementia. Sixteen aMCI patients (mean age 71 years) and fifteen healthy controls (mean age 67 years) with no differences in age or education …were subjected to increasingly complex ToM tasks and to fMRI scanning while performing the Reading the Mind in the Eyes test (RME), which attributes mental states by focusing on eye-gaze. aMCI subjects had worse performances in two second order false belief tasks, confirming the decay of ToM on the behavioral level. Despite a minor activation of some components (posterior end of the superior temporal sulcus and temporal pole) of the ToM neural circuit, no significant differences in the behavioral performances to the RME was found in aMCI compared to controls. Probably the preservation of the mirror neuron system (precentral gyrus-BA 6; Broca area - BA 44) and the stronger involvement of frontal areas (middle and medial frontal cortex and anterior cingulate cortex) supplemented the decay of part of the mentalizing neural circuit, preserving task performance. Show more

Keywords: Dementia, magnetic resonance imaging, mild cognitive impairment, mirror neurons, theory of mind (ToM)

DOI: 10.3233/JAD-2011-111256

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 25-37, 2012

Authors: Jochemsen, Hadassa M. | Geerlings, Mirjam I. | Grool, Anne M. | Vincken, Koen L. | Mali, Willem PTM. | van der Graaf, Yolanda | Muller, Majon | on behalf of the SMART Study Group

Article Type: Research Article

Abstract: High levels of angiotensin-converting-enzyme (ACE) may increase the risk of dementia through blood pressure elevation and subsequent development of cerebral small-vessel disease. However, high ACE levels may also decrease this risk through amyloid degradation which prevents brain atrophy. Within the SMART-MR study, a prospective cohort study among patients with symptomatic atherosclerotic disease, serum ACE levels were measured at baseline and a 1.5 Tesla brain MRI was performed at baseline and after on average (range) 3.9 (3.0–5.8) years of follow-up in 682 persons (mean age 58 ± 10 years). Brain segmentation was used to quantify total, deep, and periventricular white matter …lesion (WML) volume, and total brain, cortical gray matter and ventricular volume (%ICV). Lacunar infarcts were rated visually. Regression analyses were used to examine the prospective associations between serum ACE and brain measures. Patients with the highest serum ACE levels (>43.3 U/L) had borderline significantly more progression of deep WML volumes than patients with the lowest ACE levels (<21.8 U/L); mean difference (95% CI) in change was 0.20 (−0.02; 0.43) %ICV. On the contrary, patients with the highest serum ACE levels had significantly less progression of cortical brain atrophy than patients with the lowest ACE levels; mean difference (95% CI) in change was 0.78 (0.21; 1.36) %ICV. Serum ACE was not associated with subcortical atrophy, periventricular WML, or lacunar infarcts. Our results show that higher ACE activity is associated with somewhat more progression of deep WML volume, but with less progression of cortical brain atrophy. This suggests both detrimental and beneficial effects of high ACE levels on the brain. Show more

Keywords: Brain infarction, cohort studies, magnetic resonance imaging, other cerebrovascular disorders, neurodegenerative diseases, renin-angiotensin system

DOI: 10.3233/JAD-2012-111772

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 39-49, 2012

Authors: Mizwicki, Mathew T. | Menegaz, Danusa | Zhang, Jun | Barrientos-Durán, Antonio | Tse, Stephen | Cashman, John R. | Griffin, Patrick R. | Fiala, Milan

Article Type: Research Article

Abstract: Brain clearance of amyloid-β (Aβ42 ) by innate immune cells is necessary for maintenance of normal brain function. Phagocytosis of soluble Aβ42 by Alzheimer's disease (AD) macrophages is defective, recovered in all “Type I and Type II” AD patients by 1α,25(OH)2 -vitamin D3 (1,25D3) and blocked by the nuclear vitamin D receptor (VDR) antagonist (23S)-25-dehydro-1α(OH)-vitamin D3 -26,23-lactone (MK). Bisdemethoxycurcumin (BDC) is a VDR ligand and additive with 1,25D3 in promoting Aβ42 phagocytosis by Type I, but not by Type II macrophages. Here, we define the following intracellular mechanisms regulated by 1,25D3 that are associated with recovery of …phagocytosis and consistent with the selectivity of BDC: 1) 1,25D3 potentiates a 4,4-diisothiocyanostilbene-2,2-disulfonic acid-sensitive chloride channel (i.e., ClC-3) currents in both Type I and II AD macrophages, but curcumin only potentiates the currents in Type I cells; 2) 1,25D3 is particularly effective in upregulating ClC-3 mRNA expression in Type II peripheral blood mononuclear cells (PBMCs) while both 1,25D3 and the BDC analog, C180, upregulate VDR mRNA, repressed by Aβ42 in Type II PBMCs; and 3) 1,25D3-induced Aβ42 phagocytosis is attenuated by the calcium-dependent ClC-3 blocker, inositol 3,4,5,6-tetraphosphate (IP4 ), in both AD Types and by the MEK1/2 inhibitor U0126 only in Type II macrophages. VDR hydrogen/deuterium exchange coupled mass spectrometry and computational results show differences between the abilities of 1,25D3 and curcuminoids to stabilize VDR helices associated with the regulation of gene transcription. The structure-function results provide evidence that 1,25D3 activation of VDR-dependent genomic and nongenomic signaling, work in concert to recover dysregulated innate immune function in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, chloride channel, ClC-3, curcumin, hydrogen-deuterium exchange, nongenomic, nuclear vitamin D receptor, phagocytosis, 1α25(OH)2-vitamin D3

DOI: 10.3233/JAD-2012-110560

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 51-62, 2012

Authors: Mendoza-Naranjo, Ariadna | Contreras-Vallejos, Erick | Henriquez, Daniel R. | Otth, Carola | Bamburg, James R. | Maccioni, Ricardo B. | Gonzalez-Billault, Christian

Article Type: Research Article

Abstract: The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloid-β protein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show …fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD. Show more

Keywords: Actin dynamics, cofilin, cultured hippocampal neurons, cytoskeleton, LIMK1, neurodegeneration, SSH

DOI: 10.3233/JAD-2012-101575

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 63-77, 2012

Authors: Navarrete, Leonardo P. | Guzmán, Leonardo | San Martín, Aurelio | Astudillo-Saavedra, Luis | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: The neurofibrillary tangles (NFTs) generated by self-aggregation of anomalous forms of tau represent a neuropathological hallmark of Alzheimer's disease (AD). These lesions begin to form long before the clinical manifestation of AD, and its severity is correlated with cognitive impairment in patients. We focused on the search for molecules that interact with aggregated tau of the Alzheimer's type and that may block its aggregation before the formation of NFTs. We show that molecules from a family of quinolines interact specifically with oligomeric forms of tau, inhibiting their assembly into AD filaments. The quinolines 2-(4-methylphenyl)-6-methyl quinoline (THQ-4S) and 2-(4-aminophenyl)-6-methylquinoline (THQ-55) inhibited …in vitro aggregation of heparin-induced polymers of purified brain tau and aggregates of human recombinant tau. They also interact with paired helical filaments (PHFs) purified from AD postmortem brains. In vitro studies indicated a significantly lower inhibitory effect of amyloid-β42 on the aggregation, suggesting that tau aggregates are specific targets for quinoline interactions. These compounds showed highly lipophilic properties as corroborated with the analysis of total polar surface areas, and evaluation of their molecular properties. Moreover, these quinolines exhibit physical chemical properties similar to drugs able to penetrate the human brain blood barrier. Docking studies based on tau modeling, as a structural approach to the analysis of the interaction of tau-binding ligands, indicated that a C-terminal tau moiety, involved in the formation of PHFs, seems to be a site for binding of quinolines. Studies suggest the potential clinical use of these quinolines and of their derivatives to inhibit tau aggregation and possible therapeutic routes for AD. Show more

Keywords: Alzheimer's disease, filament structures, paired helical filaments, potential anti-Alzheimer's molecules, quinolines, tau protein aggregates

DOI: 10.3233/JAD-2011-110995

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 79-88, 2012

Authors: Cai, Zhiyou | Li, Benyi | Li, Keshen | Zhao, Bin

Article Type: Research Article

Abstract: Glycogen synthase kinase 3β (GSK-3β) plays a critical role in the pathogenesis of Alzheimer's disease (AD), implicating amyloid-β (Aβ) production, neurofibrillary tangle formation, and neuronal apoptosis. The activation of 5′ AMP-activated protein kinase (AMPK) has been linked to aberrant processing of amyloid-β protein precursor (AβPP), and AMPK signaling controls Aβ metabolism. It is possible that GSK-3β regulated the activation of the AMPK pathway. To test this hypothesis, the influence of GSK-3β on the expression of AβPP cleavage enzyme (BACE), Aβ, and AMPK in the SH-SY5Y and AβPP695 cells line through three inhibitors of GSK-3β was analyzed. Expression of Aβ, AMPK, …and pAMPK172 was measured by Western blot, and BACE was tested by Western blot and RT-PCR. This study demonstrated that suppression of GSK-3β activity, through specific inhibitors, dramatically down-regulated Aβ generation in human SH-SY5Y and SH-SY5Y-AβPP695 cells by enhancing AMPK activity to down-regulate Aβ. These results suggest GSK-3β inhibitors may be promising agents in the prevention and treatment of AD. Show more

Keywords: 5′ AMP-activated protein kinase, amyloid-β protein, glycogen synthase kinase 3

DOI: 10.3233/JAD-2012-111649

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 89-98, 2012

Authors: Sanders, Amy E. | Hall, Charles B. | Katz, Mindy J. | Lipton, Richard B.

Article Type: Research Article

Abstract: Cognitive reserve is invoked to explain the protective effects of education and cognitively-stimulating activities against all-cause dementia and Alzheimer's disease (AD). For non-native English speakers (n-NES), speaking English may be a cognitive activity associated with lower dementia risk. We hypothesized that n-NES have lower risk of incident dementia/AD and that educational level might modify this relationship. Participants took part in the Einstein Aging Study (Bronx, NY), a longitudinal study of aging and dementia. All (n = 1779) spoke fluent English and self-reported birthplace and whether English was their first language. n-NES additionally reported mother tongue, age of English acquisition, and …current percentile-use of a non-English language. Nested Cox proportional hazards models progressively adjusted for gender, race, education, and immigrant and marital status estimated hazard ratios (HR) for incident dementia/AD as a function of n-NES status. 390 (22%) participants were n-NES. 126 incident dementia cases occurred during 4174 person-years of follow-up (median 1.44; range 0–16); 101 individuals met criteria for probable/possible AD. There was no statistically-significant association between n-NES status and incident dementia in the fully-adjusted model (HR 1.26; 95% CI 0.76–2.09; p = 0.36). Results were similar for AD. Stratification of education into three groups revealed increased risk of dementia for n-NES with ≥ 16 years of education (HR 3.97; 95% CI 1.62–9.75; p = 0.003). We conclude that n-NES status does not appear to have an independent protective effect against incident dementia/AD, and that n-NES status may contribute to risk of dementia in an education-dependent manner. Show more

Keywords: Cohort studies, dementia, incidence, multilingualism

DOI: 10.3233/JAD-2011-111631

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 99-108, 2012

Authors: Clément, Francis | Belleville, Sylvie

Article Type: Research Article

Abstract: It is proposed that the prodromal phase of Alzheimer's disease is associated with additional brain activation in key regions involved in memory, reflecting compensatory brain plasticity. Very little is known, however, about the evolution of these compensatory mechanisms as the brain acquires more damages. We conducted an fMRI memory study measuring brain activation related to old/new (item recognition) and intact/rearranged (associative recognition) word-pair recognition paradigms in 26 persons with mild cognitive impairment (MCI) and 14 healthy older adults. The Mattis Dementia Rating Scale was used to divide persons with MCI into those with higher and lower cognitive performances. Results indicated …more brain activation in MCIs than in controls but disease severity determined which cognitive process was associated with larger activation: Persons with less severe MCI showed hyperactivation during associative recognition only, whereas persons with more severe MCI showed hyperactivation during item recognition only. These hyperactivations were found mainly in brain areas that are typically associated with retrieval mode (e.g., bilateral prefrontal cortex). These findings indicate that neural plasticity occurs during the entire MCI phase but that it is associated with different cognitive components. As they progress in the disease, individuals with MCI will experience a breakdown in the compensatory mechanisms for associative recognition accompanied by emergence of compensatory mechanisms for item recognition. Show more

Keywords: Alzheimer's disease, cognition, episodic memory, functional magnetic resonance imaging

DOI: 10.3233/JAD-2012-110426

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 109-123, 2012