Journal of Alzheimer's Disease - Volume 22, issue 1

Authors: Frost, Shaun | Martins, Ralph N. | Kanagasingam, Yogesan

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia and is clinically characterized by a progressive decline in memory, learning, and executive functions, and neuropathologically characterized by the presence of cerebral amyloid deposits. Despite a century of research, there is still no cure or conclusive premortem diagnosis for the disease. A number of symptom-modifying drugs for AD have been developed, but their efficacy is minimal and short-lived. AD cognitive symptoms arise only after significant, irreversible neural deterioration has occurred; hence there is an urgent need to detect AD early, before the onset of cognitive symptoms. An accurate, early diagnostic …test for AD would enable current and future treatments to be more effective, as well as contribute to the development of new treatments. While most AD related pathology occurs in the brain, the disease has also been reported to affect the eye, which is more accessible for imaging than the brain. AD-related proteins exist in the normal human eye and may produce ocular pathology in AD. There is some homology between the retinal and cerebral vasculatures and the retina also contains nerve cells and fibers that form a sensory extension of the brain. The eye is the only place in the body where vasculature or neural tissue is available for non-invasive optical imaging. This article presents a review of current literature on ocular morphology in AD and discusses the potential for an ocular-based screening test for AD. Show more

Keywords: Aging, amyloid-β protein, cataract, diagnosis, lens, retinal, vision disorders

DOI: 10.3233/JAD-2010-100819

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 1-16, 2010

Authors: Salmina, Alla B. | Inzhutova, Alyona I. | Malinovskaya, Natalia A. | Petrova, Marina M.

Article Type: Review Article

Abstract: Current theories state that Alzheimer's disease (AD) is a vascular disorder that initiates its pathology through cerebral microvascular abnormalities. Endothelial dysfunction caused by the injury or death of endothelial cells contributes to progression of AD. Also, functional relationships between neurons, glial cells, and vascular cells within so-called neurovascular unit are dramatically compromised in AD. Several recent studies have highlighted that endothelial cells might be the target for the toxic action of heavily aggregated proteins, glia-derived cytokines, and stimuli inducing oxidative and metabolic stress in AD brains. Here, we describe the properties of the brain endothelium that contribute to its specific …functions in the central nervous system, and how endothelial-neuronal-glial cell interactions are compromised in the pathogenesis of AD. We also discuss the ways in which functioning of endothelial cells can be modulated in cerebral microvessels. Understanding of molecular mechanisms of endothelial injury and repair in AD would give us novel diagnostic biomarkers and pharmacological targets. Show more

Keywords: Alzheimer's disease, blood-brain barrier, endothelial dysfunction, endothelial-glial interactions

DOI: 10.3233/JAD-2010-091690

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 17-36, 2010

Authors: van der Steen, Jenny T.

Article Type: Review Article

Abstract: Death with dementia is increasingly common. Although prognostication is difficult, it is an incurable life-limiting illness for which palliative care for the patient is often appropriate. Dementia patients are otherwise at risk of overtreatment with burdensome and possibly non-beneficial interventions and undertreatment of symptoms. Although recent studies indicate encouraging trends of improved palliative care, little evidence supports effectiveness of specific treatments. As of January 2010, at least 45 studies, almost all performed after 2000, have reported on treatment, comfort, symptom burden, and families' satisfaction with care. Over half (25; 56%) of these studies were in US settings, and most were …small or retrospective. Few randomized trials and prospective observational studies have been performed so far, but several promising studies have been completed recently or are underway in various countries. Guidelines for care and treatment, still mostly consensus-based, support the benefits of advance care planning, continuity of care, and family and practitioner education. Assessment tools for pain, prognosis, and family evaluations of care have been developed and some have been shown to be effective in clinical practice. With increasing numbers of well-designed, large-scale studies, research in the next decade may result in better evidence-based guidelines and practice. Show more

Keywords: Dementia, hospice care, intervention studies, palliative care, prospective studies, retrospective studies, terminal care

DOI: 10.3233/JAD-2010-100744

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 37-55, 2010

Authors: Bredesen, Dale E. | John, Varghese | Galvan, Veronica

Article Type: Review Article

Abstract: Reports from multiple laboratories have now been published analyzing the critical nature of the caspase cleavage site of amyloid-β protein precursor (AβPP) for cell death induction, synaptic loss, hippocampal atrophy, long-term potentiation, memory loss, neophobia, and other aspects of the Alzheimer's phenotype. Here we review the results and implications of these studies for the understanding of Alzheimer's disease pathophysiology and the potential development of therapeutics that target this site in AβPP.

Keywords: Alzheimer's disease, amyloid-β peptide caspases, transgenic mouse

DOI: 10.3233/JAD-2010-100537

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 57-63, 2010

Authors: Walton, J.R.

Article Type: Short Communication

Abstract: This study examines hippocampal CA1 cells from brains of aged humans, with and without Alzheimer's disease, for hyperphosphorylated tau and aluminum during early neurofibrillary tangle (NFT) formation and growth. A very small proportion of hippocampal pyramidal cells contain cytoplasmic pools within their soma that either appear homogeneous or contain short filaments (i.e., early NFTs). The cytoplasmic pools are aggregates of an aluminum/hyperphosphorylated tau complex similar to that found in mature NFTs. The photographic evidence presented combines with existing evidence to support a role for aluminum in the formation and growth of NFTs in neurons of humans with Alzheimer's disease.

Keywords: aluminium, Alzheimer's disease, hyperphosphorylated tau, neurofibrillary tangles

DOI: 10.3233/JAD-2010-100486

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 65-72, 2010

Authors: Kim, Hye Yun | Kim, YoungSoo | Han, Gyoonhee | Kim, Dong Jin

Article Type: Research Article

Abstract: It is well known that the transient and prolonged misfolding nature of amyloid-β (Aβ) makes it difficult to perform proper in vitro studies and obtain consistent results. From monomers to fibrils, the aggregated forms of Aβ are significant hallmarks in the Alzheimer's disease (AD) cascade and become the valuable targets for early diagnosis and therapy for AD. Thus, development of optimized in vitro fibrillogenic conditions to induce the desired Aβ states is essential to AD research. In this study, fifteen organic amino acid compounds (glycine, taurine, tramiprosate, and their derivatives) were employed to induce different fibrillogenic conditions for Aβ. The …fibrillogenic patterns of Aβ peptides in these compounds were analyzed by thioflavin T assay and SDS-PAGE with photoinduced cross-linking of unmodified proteins protocols, then were analyzed and compared to those obtained via transmission electron microscopy and neuronal cell viability assays. Our study suggests various compounds capable of inducing different levels of in vitro Aβ1-40 fibrillogenesis, potentially useful tools in the study of Aβ for AD. Show more

Keywords: Alzheimer's disease, amyloid-β, fibril, fibrillogenesis, monomer, oligomer, protofibril

DOI: 10.3233/JAD-2010-100183

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 73-85, 2010

Authors: Reesink, Fransje E. | Lemstra, Afina W. | van Dijk, Karin D. | Berendse, Henk W. | van de Berg, Wilma D.J. | Klein, Martin | Blankenstein, Marinus A. | Scheltens, Philip | Verbeek, Marcel M. | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: In this study, we assessed whether cerebrospinal fluid (CSF) levels of the biomarker α-synuclein have a diagnostic value in differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We also analyzed associations between CSF biomarkers and cognitive performance in DLB and in AD. We included 35 DLB patients, 63 AD patients, 18 patients with Parkinson's disease (PD), and 34 patients with subjective complaints (SC). Neuropsychological performance was measured by means of the Mini-Mental Status Examination (MMSE), Visual Association Test (VAT), VAT object-naming, Trail Making Test, and category fluency. In CSF, levels of α-synuclein, amyloid-β 1-42 (Aβ1-42 ), …total tau (tau), and tau phosphorylated at threonine 181 (ptau-181) were measured. CSF α-synuclein levels did not differentiate between diagnostic groups (p=0.16). Higher ptau-181 and higher tau levels differentiated AD from DLB patients (p< 0.05). In DLB patients, lower Aβ1-42 and higher total tau levels were found than in SC and PD patients (p< 0.05). In DLB patients, linear regression analyses of CSF biomarkers showed that lower α-synuclein was related to lower MMSE-scores (β (SE) = 6(2) and p< 0.05) and fluency (β (SE) = 4(2), p< 0.05). Ultimately, CSF α-synuclein was not a useful diagnostic biomarker to differentiate DLB and/or PD (α-synucleinopathies) from AD or SC. In DLB patients maybe lower CSF α-synuclein levels are related to worse cognitive performance. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, dementia with Lewy bodies, diagnosis, α-synuclein

DOI: 10.3233/JAD-2010-100186

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 87-95, 2010

Authors: Hong, Hyun-Seok | Hwang, Ji-Yeon | Son, Sung-Min | Kim, Yoon-Hee | Moon, Minho | Mook-Jung, Inhee

Article Type: Research Article

Abstract: Deposition of amyloid-β peptide (Aβ) and neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD), a neurodegenerative disease characterized by cognitive deficits and neuronal loss. Recently, calcineurin (CaN) has been reported as a potential modulator of memory function, synaptic plasticity, and neural degeneration in brains of AD animal models. In the present study, we examined the relationship between Aβ accumulations and CaN activity in brains of the AβPP/PS1 double transgenic mice. Treatment with FK506, a CaN inhibitor, significantly reduces Aβ burden and restores synaptic proteins (synaptophysin and postsynaptic density protein-95; PSD-95) while inducing matrix metallopeptidase-9 (MMP-9) expression in GFAP-positive astrocytes …in the brain. These results suggest a role of FK506 and control of CaN activity in neuroprotection associated with Aβ deposition in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, AβPP/PS1 double transgenic mouse, calcineurin, FK506, MMP-9

DOI: 10.3233/JAD-2010-100261

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 97-105, 2010

Authors: Yang, Shi-Gao | Zhang, Xi | Sun, Xiao-Sia | Ling, Tie-Jun | Feng, Ying | Du, Xue-Ying | Zhao, Min | Yang, Yang | Xue, Di | Wang, Li | Liu, Rui-Tian

Article Type: Research Article

Abstract: Amyloid-β (Aβ) plays a pivotal role in Alzheimer's disease (AD) pathogenesis and in toxic mechanisms such as oxidative stress, mitochondrial dysfunction, calcium turbulence, and apoptosis induction. Therefore, interfering with Aβ aggregation has long been one of the most promising strategies for AD treatment. Ecdysterones (ECRs) are steroidal hormones in insects and terrestrial plants that have high structural diversity and multiple beneficial pharmacological activities. Here, we studied the effects of six ECRs on Aβ aggregation and cytotoxicity. Two ECRs with an acetoxyl group at the 2 or 3 position and saturated chains as side groups showed apparent promotion of Aβ42 …fibrilization, resulting in less Aβ42 oligomers in the samples. Another three with unsaturated side chains clearly inhibited Aβ aggregation and disaggregated preformed fibrils, but increased the Aβ42 oligomer levels. Nevertheless, our MTT results showed that all ECRs tested inhibited Aβ42 -induced cytotoxicity. This protective activity may be partly attributable to ECR-mediated amelioration of Aβ42 -induced release of reactive oxygen species. Taken together, our findings suggest that ECRs, a series of natural compounds in many plants and insects, have therapeutic potential in AD and that the deduced structure-activity relationships may be beneficial in drug design for the treatment of AD and other amyloidoses. Show more

Keywords: Aggregation, Alzheimer's disease, amyloid-β, ecdysterone, Klaseopsis chinensis, neurotoxicity

DOI: 10.3233/JAD-2010-100621

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 107-117, 2010

Authors: Steinacker, Petra | Klafki, Hans | Lehnert, Stefan | Jesse, Sarah | v. Arnim, Christine A.F. | Tumani, Hayrettin | Pabst, Alice | Kretzschmar, Hans A. | Wiltfang, Jens | Otto, Markus

Article Type: Research Article

Abstract: The clinical diagnosis of Creutzfeldt-Jakob disease (CJD) can be supported by several biochemical markers in cerebrospinal fluid (CSF) such as 14-3-3 proteins and tau protein. Unfortunately, none of the currently known markers are suited for screening or seems to be directly related to the pathophysiological process. A marker fulfilling these criteria might facilitate the early detection and might also serve in monitoring drug efficacy. Recently, the extracellular signal-regulated kinase ERK1/2 was detected in CSF of patients with neuropsychiatric disorders. Furthermore, ERK1/2 was reported to be activated in brains of animals infected with pathological prion protein. Therefore, we investigated CSF of …19 patients with CJD, 23 patients with other dementias including patients with Alzheimer's disease, and 12 patients with other neurological disorders. The measurement of ERK1/2 in the CSF samples was performed with an electrochemiluminescence assay and Western immunoblot. ERK1/2 and doubly phosphorylated ERK1/2 (pERK1/2) were detected in all patient groups. Significantly elevated mean levels of total ERK1/2 and pERK1/2 were found in the CJD patients. This increase was also observed in a CJD case that was negative for 14-3-3 protein or in CJD cases that had low levels of tau protein. Western immunoblot analysis suggested that ERK2 was the predominant form of ERKs present in our CSF samples. This pilot study suggests that ERK1/2 is a potential CSF biomarker for CJD, directly associated with the pathophysiological processes. Analysis of larger sample cohorts including other diseases with rapid neurodegeneration are required to confirm our findings. Show more

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, Creutzfeldt-Jakob disease, duplex electrochemiluminescence assay, extracellular signal-regulated kinase ERK1/2

DOI: 10.3233/JAD-2010-100030

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 119-128, 2010