Journal of Alzheimer's Disease - Volume 41, issue 3

Authors: Tales, Andrea | Wilcock, Gordon K. | Phillips, Judith E. | Bayer, Antony

Article Type: Review Article

Abstract: Multi-disciplinary research has revealed evidence of significant abnormality in a much wider range and level of information processing than that currently definitive for amnestic mild cognitive impairment (MCI). This raises the possibility that the contemporary approach to MCI is inappropriately delimited, and the true nature and extent of brain dysfunction and thus disease burden, underestimated. It follows therefore that the closely related concept of subjective cognitive impairment (SCI) may be similarly constrained. Although research into the wider range of potential brain dysfunction in MCI and SCI is in its infancy, as yet precluding systematic reviews, we present here findings to …prompt debate about SCI with respect to its clinical assessment and its personal and societal burden. Show more

Keywords: Mild cognitive impairment, subjective cognitive impairment

DOI: 10.3233/JAD-132414

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 655-661, 2014

Authors: Rosen, Allyson C.

Article Type: Review Article

DOI: 10.3233/JAD-141293

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 663-664, 2014

Authors: Tales, Andrea | Wilcock, Gordon K. | Phillips, Judith E. | Bayer, Antony

Article Type: Review Article

DOI: 10.3233/JAD-141294

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 665-666, 2014

Authors: Shea, Thomas B. | Rogers, Eugene

Article Type: Editorial

Abstract: Nutrition exerts a pervasive impact on normal and pathological conditions of the nervous system throughout life. Maternal folate supplementation during pregnancy has reduced developmental disorders of the nervous system, but may have also fostered an increase in individuals harboring genetic polymorphisms that compromise folate usage. Such individuals may harbor a lifetime requirement for additional dietary folate, often not met beyond peri/postnatal periods. An increased association of such polymorphisms has been detected in individuals with autism. Prenatal nutritional supplementation may have inadvertently established latent conditions that, in the absence of continued supplementation, may lead to age-related cognitive decline.

Keywords: Dementia, genetic risk, methylene tetrahydrofolate reductase, nutrition, polymorphism, prenatal

DOI: 10.3233/JAD-132675

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 667-669, 2014

Authors: Rudrabhatla, Parvathi

Article Type: Review Article

Abstract: Neuronal cytoskeletal proteins such as neurofilaments (NFs) and tau are aberrantly and hyperphosphorylated in neurodegeneration. Under normal physiological conditions, NFs are synthesized in the cell bodies and phosphorylated and transported in the axonal compartment. However, under neurodegenerative disorders such as Alzheimer's disease (AD), spinal cord motor neuron inclusions of amyotrophic lateral sclerosis, Lewy bodies of Parkinson's disease, Pick's disease, Charcot-Marie-Tooth disease, and diabetic neuropathy, NFs are aberrantly and hyperphosphorylated in cell bodies. The proline directed protein kinases, such as cyclin-dependent protein kinase 5, mitogen activated protein kinase, and glycogen synthase kinase 3β, and the non proline-directed kinases, such as casein …kinase 1, are deregulated in AD. Moreover, the reversible phosphorylation by protein phosphatase, PP2A, which mainly carries out the dephosphorylation of tau and NFs, is down regulated in AD brain. The aberrant phosphorylation of cytoskeletal proteins such as tau and NFs results in the axonal transport defects in neurodegeneration. The peptidyl-prolyl isomerase Pin1 plays a regulatory role in the post-phosphorylation mechanism of neuronal cytoskeletal proteins in AD brain. Possible therapeutic interventions for neurodegenerative disorders are 1) inhibition of proline-directed kinases, 2) activation of protein phosphatases such as PP2A, and 3) modulation of peptidyl-prolyl isomerases such as Pin1. Here, I discuss the regulation of neuronal cytoskeletal proteins under physiology and pathology. Show more

Keywords: Axonal transport, cytoskeleton, neurofilament, PP2A, proline-directed kinases, synuclein, tangles, tau, TDP43

DOI: 10.3233/JAD-130794

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 671-684, 2014

Authors: Falahati, Farshad | Westman, Eric | Simmons, Andrew

Article Type: Review Article

Abstract: Machine learning algorithms and multivariate data analysis methods have been widely utilized in the field of Alzheimer's disease (AD) research in recent years. Advances in medical imaging and medical image analysis have provided a means to generate and extract valuable neuroimaging information. Automatic classification techniques provide tools to analyze this information and observe inherent disease-related patterns in the data. In particular, these classifiers have been used to discriminate AD patients from healthy control subjects and to predict conversion from mild cognitive impairment to AD. In this paper, recent studies are reviewed that have used machine learning and multivariate analysis in …the field of AD research. The main focus is on studies that used structural magnetic resonance imaging (MRI), but studies that included positron emission tomography and cerebrospinal fluid biomarkers in addition to MRI are also considered. A wide variety of materials and methods has been employed in different studies, resulting in a range of different outcomes. Influential factors such as classifiers, feature extraction algorithms, feature selection methods, validation approaches, and cohort properties are reviewed, as well as key MRI-based and multi-modal based studies. Current and future trends are discussed. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, classification, machine learning, magnetic resonance imaging, mild cognitive impairment, multivariate analysis, positron emission tomography

DOI: 10.3233/JAD-131928

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 685-708, 2014

Authors: Testi, Silvia | Peluso, Silvio | Fabrizi, Gian Maria | Antenora, Antonella | Russo, Cinzia Valeria | Pappatà, Sabina | Padovani, Alessandro | Ferrarini, Moreno | Filla, Alessandro

Article Type: Short Communication

Abstract: PSEN1 gene mutations represent the first cause of familiar early-onset Alzheimer's disease (EOAD). More than 190 mutations in PSEN1 have been reported to date. The clinical phenotype is mainly characterized by cognitive decline but movement disorders have been rarely described. We report a novel PSEN1 mutation (p.Thr147Pro) responsible for a sporadic early-onset dementia with prominent cerebellar symptoms, resembling a spinocerebellar syndrome. Neuroradiological and cerebrospinal fluid biomarkers examinations were performed on the patient, showing typical findings of EOAD and suggesting the pathogenicity of the novel mutation. Our study widens the number of unusual phenotypes related to PSEN1 mutations.

Keywords: Ataxia, early onset Alzheimer's disease, dominantly-inherited spinocerebellar ataxias, human PSEN1 protein

DOI: 10.3233/JAD-140081

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 709-714, 2014

Authors: Hartmann, Tobias | van Wijk, Nick | Wurtman, Richard J. | Olde Rikkert, Marcel G.M. | Sijben, John W.C. | Soininen, Hilkka | Vellas, Bruno | Scheltens, Philip

Article Type: Research Article

Abstract: Recently, a biomarker panel of 10 plasma lipids, including 8 phosphatidylcholine species, was identified that could predict phenoconversion from cognitive normal aged adults to amnestic mild cognitive impairment or Alzheimer's disease (AD) within 2–3 years with >90% accuracy. The reduced levels of these plasma phospholipids could reflect altered phospholipid metabolism in the brain and periphery. We show that a 24-week nutritional intervention in drug-naïve patients with very mild to mild AD significantly increased 5 of the 7 measured biomarker phosphatidylcholine species. By providing nutrients which normally rate-limit phospholipid synthesis, this nutritional intervention could be useful in asymptomatic subjects with a …plasma lipid biomarker profile prognostic of AD. Show more

Keywords: Alzheimer's disease, membranes, nutritional intervention, phosphatidylcholine, plasma phospholipids, prognostic biomarkers, synaptic dysfunction

DOI: 10.3233/JAD-141137

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 715-717, 2014

Authors: Marshall, Gad A. | Lorius, Natacha | Locascio, Joseph J. | Hyman, Bradley T. | Rentz, Dorene M. | Johnson, Keith A. | Sperling, Reisa A. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Impairment in instrumental activities of daily living (IADL) heralds the transition from mild cognitive impairment (MCI) to dementia and is a major source of burden for both the patient and caregiver. Objective: To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. Methods: Two hundred and twenty nine CN, 395 MCI, and 188 AD dementia subjects participating in the Alzheimer’s Disease Neuroimaging Initiative underwent baseline magnetic resonance imaging, baseline lumbar puncture, and clinical …assessments, including the Functional Activities Questionnaire used to measure IADL, every 6 to 12 months up to 3 years. General linear regression and mixed effects models were employed. Results: IADL impairment was associated with the interactions between lower inferior temporal cortical thickness and diagnosis (p < 0.0001), greater lateral occipital cortical thickness and diagnosis (p < 0.0001), and greater amyloid-β 1-42 (Aβ1-42 ) and diagnosis (p = 0.0002) at baseline (driven by AD dementia). Lower baseline supramarginal (p = 0.02) and inferior temporal (p = 0.05) cortical thickness, lower Aβ1-42 (p < 0.0001), and greater total tau (t-tau) (p = 0.02) were associated with greater rate of IADL impairment over time. Conclusions: Temporal atrophy is associated with IADL impairment in mild AD dementia at baseline, while baseline parietal and temporal atrophy, lower CSF Aβ1-42 , and greater t-tau predict worsening IADL impairment over time across the AD spectrum. These results emphasize the importance of assessing IADL at the stage of MCI and even at the transition from CN to MCI. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, instrumental activities of daily living, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-132768

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 719-728, 2014

Authors: Chu, Jin | Lauretti, Elisabetta | Craige, Caryne P. | Praticò, Domenico

Article Type: Research Article

Abstract: Accumulation of neurotoxic amyloid-β (Aβ) is a major hallmark of Alzheimer's disease (AD) pathology and an important player in its clinical manifestations. Formation of Aβ is controlled by the availability of an enzyme called γ-secretase. Despite its blockers being attractive therapeutic tools for lowering Aβ, this approach has failed because of their serious toxic side-effects. The discovery of the γ-secretase activating protein (GSAP), a co-factor for this protease which facilitates Aβ production without affecting other pathways responsible for the toxicity, is giving us the opportunity to develop a safer anti-Aβ therapy. In this study we have characterized the effect of …Imatinib, an inhibitor of GSAP, in the 3×Tg mice, a mouse model of AD with plaques and tangles. Compared with controls, mice receiving the drug had a significant reduction in brain Aβ levels and deposition, but no changes in the steady state levels of AβPP, BACE-1, ADAM-10, or the four components of the γ-secretase complex. By contrast, Imatinib-treated animals had a significant increase in CTF-β and a significant reduction in GSAP expression levels. Additionally, we observed that tau phosphorylation was reduced at specific epitopes together with its insoluble fraction. In vitro studies confirmed that Imatinib prevents Aβ formation by modulating γ-secretase activity and GSAP levels. Our findings represent the first in vivo demonstration of the biological role that GSAP plays in the development of the AD-like neuropathologies. They establish this protein as a viable target for a safer anti-Aβ therapeutic approach in AD. Show more

Keywords: Amyloid-β, γ-secretase, imatinib, tau protein, transgenic mice

DOI: 10.3233/JAD-140105

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 729-737, 2014