Journal of Alzheimer's Disease - Volume 53, issue 1

Authors: Hensley, Kenneth | Kursula, Petri

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) has long been viewed as a pathology that must be caused either by aberrant amyloid-β protein precursor (AβPP) processing, dysfunctional tau protein processing, or a combination of these two factors. This is a reasonable assumption because amyloid-β peptide (Aβ) accumulation and tau hyperphosphorylation are the defining histological features in AD, and because AβPP and tau mutations can cause AD in humans or AD-like features in animal models. Nonetheless, other protein players are emerging that one can argue are significant etiological players in subsets of AD and potentially novel, druggable targets. In particular, the microtubule-associated protein CRMP2 (collapsin …response mediator protein-2) bears striking analogies to tau and is similarly relevant to AD. Like tau, CRMP2 dynamically regulates microtubule stability; it is acted upon by the same kinases; collects similarly in neurofibrillary tangles (NFTs); and when sequestered in NFTs, complexes with critical synapse-stabilizing factors. Additionally, CRMP2 is becoming recognized as an important adaptor protein involved in vesicle trafficking, amyloidogenesis and autophagy, in ways that tau is not. This review systematically compares the biology of CRMP2 to that of tau in the context of AD and explores the hypothesis that CRMP2 is an etiologically significant protein in AD and participates in pathways that can be rationally engaged for therapeutic benefit. Show more

Keywords: Alzheimer’s disease, autophagy, collapsin response mediator protein-2, cyclin-dependent kinase, microtubule-associated protein tau, therapeutic, vesicle transport

DOI: 10.3233/JAD-160076

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 1-14, 2016

Authors: El Gaamouch, Farida | Jing, Ping | Xia, Jiahong | Cai, Dongming

Article Type: Review Article

Abstract: Brain lipid homeostasis plays an important role in Alzheimer’s disease (AD) and other neurodegenerative disorders. Aggregation of amyloid-β peptide is one of the major events in AD. The complex interplay between lipids and amyloid-β accumulation has been intensively investigated. The proportions of lipid components including phospholipids, sphingolipids, and cholesterol are roughly similar across different brain regions under physiological conditions. However, disruption of brain lipid homeostasis has been described in AD and implicated in disease pathogenesis. Moreover, studies suggest that analysis of lipid composition in plasma and cerebrospinal fluid could improve our understanding of the disease development and progression, which could …potentially serve as disease biomarkers and prognostic indicators for AD therapies. Here, we summarize the functional roles of AD risk genes and lipid regulators that modulate brain lipid homeostasis including different lipid species, lipid complexes, and lipid transporters, particularly their effects on amyloid processing, clearance, and aggregation, as well as neuro-toxicities that contribute to AD pathogenesis. Show more

Keywords: Alzheimer’s disease, apolipoproteins, lipids, amyloid, cholesterol, phospholipids

DOI: 10.3233/JAD-160169

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 15-29, 2016

Authors: Trojano, Luigi | Gainotti, Guido

Article Type: Review Article

Abstract: Drawing is a multicomponential process that can be impaired by many kinds of brain lesions. Drawing disorders are very common in Alzheimer’s disease and other forms of dementia, and can provide clinical information for the distinction of the different dementing diseases. In our review we started from an overview of the neural and cognitive bases of drawing, and from a recollection of the drawing tasks more frequently used for assessing individuals with dementia. Then, we analyzed drawing disorders in dementia, paying special attention to those observed in Alzheimer’s disease, from the prodromal stages of the amnesic mild cognitive impairment to …the stages of full-blown dementia, both in the sporadic forms with late onset in the entorhino-hippocampal structures and in those with early onset in the posterior neocortical structures. We reviewed the drawing features that could differentiate Alzheimer’s disease from vascular dementia and from the most frequent forms of degenerative dementia, namely frontotemporal dementia and Lewy body disease. Finally, we examined some peculiar aspects of drawing disorders in dementia, such as perseverations, rotations, and closing-in. We argue that a careful analysis of drawing errors helps to differentiate the different forms of dementia more than overall accuracy in drawing. Show more

Keywords: Alzheimer’s disease, constructional apraxia, drawing disorders, frontotemporal dementia, Lewy body disease, vascular dementia

DOI: 10.3233/JAD-160009

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 31-52, 2016

Authors: Schuster, Judith | Funke, Susanne Aileen

Article Type: Review Article

Abstract: Protein misfolding and aggregation are fundamental features of the majority of neurodegenerative diseases, like Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia, and prion diseases. Proteinaceous deposits in the brain of the patient, e.g., amyloid plaques consisting of the amyloid-β (Aβ) peptide and tangles composed of tau protein, are the hallmarks of AD. Soluble oligomers of Aβ and tau play a fundamental role in disease progression, and specific detection and quantification of the respective oligomeric proteins in cerebrospinal fluid may provide presymptomatically detectable biomarkers, paving the way for early diagnosis or even prognosis. Several studies on the development of techniques for …the specific detection of Aβ oligomers were published, but some of the existing tools do not yet seem to be satisfactory, and the study results are contradicting. The detection of oligomers is challenging due to their polymorphous and unstable nature, their low concentration, and the presence of competing proteins and Aβ monomers in body fluids. Here, we present an overview of the current state of the development of methods for Aβ oligomer specific detection and quantitation. The methods are divided in the three subgroups: (i) enzyme linked immunosorbent assays (ELISA), (ii) methods for single oligomer detection, and (iii) others, which are mainly biosensor based methods. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, biomarkers, diagnosis, protein misfolding diseases, therapy monitoring

DOI: 10.3233/JAD-151029

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 53-67, 2016

Authors: Neugroschl, Judith | Sewell, Margaret | De La Fuente, Angelica | Umpierre, Mari | Luo, Xiaodong | Sano, Mary

Article Type: Short Communication

Abstract: In dementia trials, minority participation is low. We assessed attitudes toward research in a community based urban poor minority sample of elderly adults attending senior center talks using the 7-item Research Attitudes Questionnaire (RAQ). Presentations on cognitive aging were given at senior centers, and 123 attendees completed the RAQ-7. On trust and safety questions, a significant minority (42–48%) responded neutrally or negatively. Encouragingly, on questions concerning the importance of research, 72–81% answered positively. More work can be done to capitalize on these findings to engage and foster trust, and this can be a focus of outreach.

Keywords: Attitude, dementia, elderly, memory, minority, research

DOI: 10.3233/JAD-151072

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 69-72, 2016

Authors: Marín-Muñoz, Juan | Noguera-Perea, Ma Fuensanta | Gómez-Tortosa, Estrella | López-Motos, David | Antequera-Torres, Martirio | Martínez-Herrada, Begoña | Manzanares-Sánchez, Salvadora | Vivancos-Moreau, Laura | Legaz-García, Agustina | Rábano-Gutiérrez del Arroyo, Alberto | Antúnez-Almagro, Carmen

Article Type: Short Communication

Abstract: Mutations in the presenilin 2 gene (PS2 ) are an extremely rare cause of early-onset autosomal dominant Alzheimer’s disease (AD), accounting for only 5% of these families. These cases represent a particular model of AD, and the scarcity of reports on their clinical phenotypes makes them of great interest. We report a family with early-onset autosomal dominant AD in four members, where the two living siblings were found to carry the novel PS2 mutation Gly212Val (exon 7, transmembrane domain IV) with highly predicted pathogenicity. Age at onset ranged from 60 to 65 years and three of the cases died …between ages 74 and 76 years. Clinical phenotype was quite homogeneous among affected members of the family, and overall features, including cognitive decline, tau/p-tau and amyloid-β cerebrospinal fluid markers, neuroimaging, and neuropathology were consistent with typical AD. Lewy bodies were present but restricted to the amygdala. Show more

Keywords: Early-onset dementia, familial Alzheimer’s disease, neurogenetics, presenilin 2 mutation

DOI: 10.3233/JAD-160050

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 73-78, 2016

Authors: Brodtmann, Amy | Pemberton, Hugh | Darby, David | Vogel, Adam P.

Article Type: Research Article

Abstract: Apraxia of speech (AOS) can be the presenting symptom of neurodegenerative disease. The position of primary progressive AOS in the nosology of the dementias is still controversial. Despite seeing many specialists, patients are often misdiagnosed, in part due to a lack of quantitative measures of speech dysfunction. We present a single case report of a patient presenting with AOS, including acoustic analysis, language assessment, and brain imaging. A 52-year-old woman presenting with AOS had remained undiagnosed for 6 years despite seeing 8 specialists. Results of her MRI scans, genetic testing, and computerized speech analysis are provided. AOS is an underdiagnosed …clinical syndrome causing great distress to patients and families. Using acoustic analysis of speech may lead to improved diagnostic accuracy. AOS is a complex entity with an expanding phenotype, and quantitative clinical measures will be critical for detection and to assess progression. Show more

Keywords: Apraxia of speech, corticobasal syndrome, frontotemporal dementia, voice acoustic analysis

DOI: 10.3233/JAD-160069

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 79-83, 2016

Authors: Moreira, Afonso | Diógenes, Maria José | de Mendonça, Alexandre | Lunet, Nuno | Barros, Henrique

Article Type: Research Article

Abstract: Cocoa-related products like chocolate have taken an important place in our food habits and culture. In this work, we aim to examine the relationship between chocolate consumption and cognitive decline in an elderly cognitively healthy population. In the present longitudinal prospective study, a cohort of 531 participants aged 65 and over with normal Mini-Mental State Examination (MMSE; median 28) was selected. The median follow-up was 48 months. Dietary habits were evaluated at baseline. The MMSE was used to assess global cognitive function at baseline and at follow-up. Cognitive decline was defined by a decrease ≥ 2 points in the MMSE …score between evaluations. Relative risk (RR) and 95% confidence interval (95% CI) estimates were adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes. Chocolate intake was associated with a lower risk of cognitive decline (RR = 0.59, 95% CI 0.38–0.92). This protective effect was observed only among subjects with an average daily consumption of caffeine lower than 75 mg (69% of the participants; RR = 0.50, 95% CI 0.31–0.82). To our knowledge, this is the first prospective cohort study to show an inverse association between regular long-term chocolate consumption and cognitive decline in humans. Show more

Keywords: Adenosine A2A receptors, Alzheimer’s disease, chocolate, cognition, prevention, theobromine

DOI: 10.3233/JAD-160142

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 85-93, 2016

Authors: Perkins, Michelle | Wolf, Andrew B. | Chavira, Bernardo | Shonebarger, Daniel | Meckel, J.P. | Leung, Lana | Ballina, Lauren | Ly, Sarah | Saini, Aman | Jones, T. Bucky | Vallejo, Johana | Jentarra, Garilyn | Valla, Jon

Article Type: Research Article

Abstract: The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer’s disease (AD). Apolipoprotein E ɛ 4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, …we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD. Show more

Keywords: Alzheimer’s disease, APOE, biomarker, energy metabolism, glucose, ketones, mitochondria, monocarboxylate, neurodegeneration, posterior cingulate

DOI: 10.3233/JAD-151205

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 95-106, 2016

Authors: Willemse, Eline A.J. | Durieux-Lu, Sisi | van der Flier, Wiesje M. | Pijnenburg, Yolande A.L. | de Jonge, Robert | Teunissen, Charlotte E.

Article Type: Research Article

Abstract: Progranulin (PGRN) levels in blood and cerebrospinal fluid (CSF) are increasingly studied as potential markers for neurodegenerative disorders. We aimed to 1) characterize two commercially available PGRN ELISAs on several assay validation parameters, 2) assess the stability of PGRN in serum and CSF under pre-analytical conditions, and 3) compare stability in the two assays. Intra- and inter-assay variation, inter-lot variation, linearity, lower limit of detection, and kit correlations were assessed for the Adipogen and R&D PGRN ELISA kits. Blood and serum samples were experimentally exposed to ≤9 freeze/thaw cycles, delayed processing for ≤24 h at room temperature and 4°C, and to …temperature stability tests for ≤3 weeks at –20°C, 4°C, room temperature, and 37°C. Both commercial PGRN ELISA kits showed acceptable ranges for intra- and inter-assay variation, where the R&D kit performed more accurate than the Adipogen kit, especially for inter-assay variation (intra-assay serum: 6.7 and 8.3%, respectively; inter-assay serum: 9.2 and 21.0%; intra-assay CSF: 3.6 and 12.0%; inter-assay CSF: 16.0 and 44.5%). Absolute serum PGRN concentrations were 1.9-fold higher in Adipogen than R&D (p  < 0.001) and strongly correlated between both kits (ρ = 0.86, p  < 0.0001) and CSF PGRN levels were on the borderline of detection in both kits. PGRN was typically stable under all pre-analytical conditions addressed, although two weeks at 37°C resulted in decreased PGRN concentrations in CSF, only when using the Adipogen kit. These results support further examination of PGRN as a potential marker in neurodegenerative diseases, since PGRN is stable in serum and CSF and can be measured using ELISA kits from several providers. Show more

Keywords: Cerebrospinal fluid, human progranulin protein, ELISA, method comparison, pre-analytical variation, protein stability, serum

DOI: 10.3233/JAD-160061

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 107-116, 2016