Journal of Alzheimer's Disease - Volume 39, issue 3

Authors: Tsigelny, Igor F. | Sharikov, Yuriy | Kouznetsova, Valentina L. | Greenberg, Jerry P. | Wrasidlo, Wolfgang | Gonzalez, Tania | Desplats, Paula | Michael, Sarah E. | Trejo-Morales, Margarita | Overk, Cassia R. | Masliah, Eliezer

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is associated with the formation of toxic amyloid-β (Aβ)42 oligomers, and recent evidence supports a role for Aβ dimers as building blocks for oligomers. Molecular dynamics simulation studies have identified clans for the dominant conformations of Aβ42 forming dimers; however, it is unclear if a larger spectrum of dimers is involved and which set(s) of dimers might evolve to oligomers verse fibrils. Therefore, for this study we generated multiple structural conformations of Aβ42 , using explicit all-atom molecular dynamics, and then clustering the different structures based on key conformational similarities. Those matching a selection threshold …were then used to model a process of oligomerization. Remarkably, we showed a greater diversity in Aβ dimers than previously described. Depending on the clan family, different types of Aβ dimers were obtained. While some had the tendency to evolve into oligomeric rings, others formed fibrils of diverse characteristics. Then we selected the dimers that would evolve to membranephilic annular oligomers. Nearly one third of the 28 evaluated annular oligomers had the dimer interfaces between the neighboring Aβ42 monomers with possible salt bridges between the residue K28 from one side and either residue E22 or D23 on the other. Based on these results, key amino acids were identified for point mutations that either enhanced or suppressed the formation and toxicity of oligomer rings. Our studies suggest a greater diversity of Aβ dimers. Understanding the structure of Aβ dimers might be important for the rationale design of small molecules that block formation of toxic oligomers. Show more

Keywords: Dimers, molecular dynamics, neurodegeneration, oligomers, synaptoxicity

DOI: 10.3233/JAD-131589

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 583-600, 2014

Authors: Chung, Chih-Ping | Beggs, Clive | Wang, Pei-Ning | Bergsland, Niels | Shepherd, Simon | Cheng, Chun-Yu | Ramasamy, Deepa P. | Dwyer, Michael G. | Hu, Han-Hwa | Zivadinov, Robert

Article Type: Research Article

Abstract: To determine whether jugular venous reflux (JVR) is associated with cerebral white matter changes (WMCs) in individuals with Alzheimer's disease (AD), we studied 12 AD patients 24 mild cognitive impairment (MCI) patients, and 17 elderly age- and gender-matched controls. Duplex ultrasonography and 1.5T MRI scanning was applied to quantify cerebral WMCs [T2 white matter (WM) lesion and dirty-appearing-white-matter (DAWM)]. Subjects with severe JVR had more frequently hypertension (p = 0.044), more severe WMC, including increased total (p = 0.047) and periventricular DAWM volumes (p = 0.008), and a trend for increased cerebrospinal fluid volumes (p = 0.067) compared with the …other groups. A significantly decreased (65.8%) periventricular DAWM volume (p = 0.01) in the JVR-positive AD individuals compared with their JVR-negative counterparts was detected. There was a trend for increased periventricular and subcortical T2 WMC lesion volumes in the JVR-positive AD individuals compared with their JVR-negative counterparts (p = 0.073). This phenomenon was not observed in either the control or MCI groups. In multiple regression analysis, the increased periventricular WMC lesion volume and decreased DAWM volume resulted in 85.7% sensitivity and 80% specificity for distinguishing between JVR-positive and JVR-negative AD patients. These JVR-WMC association patterns were not seen in the control and MCI groups. Therefore, this pilot study suggests that there may be an association between JVR and WMCs in AD patients, implying that cerebral venous outflow impairment might play a role in the dynamics of WMCs formation in AD patients, particularly in the periventricular regions. Further longitudinal studies are needed to confirm and validate our findings. Show more

Keywords: Alzheimer's disease, Doppler ultrasonography, jugular veins, leukoaraiosis, magnetic resonance imaging

DOI: 10.3233/JAD-131112

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 601-609, 2014

Authors: Magnin, Eloi | Paquet, Claire | Formaglio, Maité | Croisile, Bernard | Chamard, Ludivine | Miguet-Alfonsi, Carole | Tio, Gregory | Dumurgier, Julien | Roullet-Solignac, Isabelle | Sauvée, Mathilde | Thomas-Antérion, Catherine | Vighetto, Alain | Hugon, Jacques | Vandel, Pierre

Article Type: Research Article

Abstract: Background: Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimer’s disease (AD). Objective: The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD). Methods: CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67). and aMCI-AD (n = 27). Results: p-Tau181 levels …were higher in the lvPPA-AD group than in the aMCI-AD group (p < 0.05). Total tau levels were higher in the lvPPA-AD group versus those in the nlAD (p < 0.05) and aMCI-AD (p < 0.001) groups. Conclusions: These results suggest a more pronounced involvement of a taupathy in lvPPA-AD compared to aMCI-AD and a more important neuronal death in lvPPA-AD than in nlAD or aMCI-AD. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid markers, logopenic, mild cognitive impairment, primary progressive aphasia

DOI: 10.3233/JAD-131382

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 611-616, 2014

Authors: Yanagisawa, Daijiro | Taguchi, Hiroyasu | Ibrahim, Nor Faeizah | Morikawa, Shigehiro | Shiino, Akihiko | Inubushi, Toshiro | Hirao, Koichi | Shirai, Nobuaki | Sogabe, Takayuki | Tooyama, Ikuo

Article Type: Research Article

Abstract: Fluorine-19 magnetic resonance imaging (19 F MRI) could be a promising approach for imaging amyloid deposition in the brain. However, the required features of a 19 F MRI probe for amyloid detection remain unclear. In the present study, we investigated a series of compounds as potent 19 F probes that could prevent the reduction in MR signal when bound to amyloid plaques in the brain. Each compound consists of styrylbenzoxazole as a core structure linked by a different length of polyethylene glycol (PEG) chain to one of three types of fluorine-labeled group: a trifluoroethoxy group, a hexafluoroisopropoxy group, or a …3′,5′-bis(trifluoromethyl)benzylamino group. Among these compounds, 6-(3′,6′,9′,15′,18′,21′-heptaoxa-23′,23′,23′-trifluoro tricosanyloxy)-2-(4′-dimethylaminostyryl)benzoxazole [compound 3b (m = 6)], which has a trifluoroethoxy group with seven ethylene glycol groups in the PEG chain, showed significant 19 F MR signals in the brains of AβPPswe/PS1dE9 double-transgenic mice, but not wild-type mice. This suggested that compound 3b (m = 6) could be a useful 19 F MRI probe for amyloid detection. Furthermore, this study identified the most effective length of PEG chain between the fluorine-labeled group and the core structure to ensure a strong MR signal when the probe is bound to amyloid plaques. Show more

Keywords: Alzheimer's disease, amyloid deposition, amyloid imaging, fluorine-19 MRI, magnetic resonance imaging

DOI: 10.3233/JAD-131025

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 617-631, 2014

Authors: Stella, Florindo | Radanovic, Márcia | Aprahamian, Ivan | Canineu, Paulo Renato | de Andrade, Larissa Pires | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD) and mild cognitive impairment (MCI), apathy was associated with faster clinical deterioration. Studies involving neurobiological correlates such as neuroimaging and biomarkers have presented distinct results. Objective: This work aimed to analyze neurobiological correlates of apathy in AD and MCI based on evidence from the literature involving brain neuroimaging and classical AD biomarkers. Methods: This review comprised studies published from 1996 to June 2013 from the Pubmed database. The studies were divided into Part I (neuroimaging) and Part II (chemical biomarkers). The analysis included the identification of brain regions involved and assessments …of apathy and cognition. We found 68 publications: 33 fulfilled the inclusion criteria; 35 were case reports or were not clear about the measurements of apathy and were excluded. From the 33 eligible studies, 26 were classified into part I, and 7 studies were included in part II. We created specific criteria to appropriately classify the quality level of each publication. Results: Prefrontal regions and the anterior cingulate were the leading brain areas associated with apathy in AD and MCI. Other regions, including cortical and subcortical structures, have also been implicated in this syndrome. Conclusions: Abnormalities in frontal regions (associated with impairments in planning and decision making) and anterior cingulate (related to emotional blunting and loss of motivation) were the crucial structures associated with apathy in AD and MCI. Show more

Keywords: Apathy, Alzheimer's disease, mild cognitive impairment, neurobiological correlates, neuroimaging, review

DOI: 10.3233/JAD-131385

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 633-648, 2014

Authors: Camero, Sergio | Benítez, María J. | Barrantes, Alejandro | Ayuso, José M. | Cuadros, Raquel | Ávila, Jesús | Jiménez, Juan S.

Article Type: Research Article

Abstract: Tau protein has been proposed as a trigger of Alzheimer's disease once it is hyperphosphorylated. However, the role that native tau forms play inside the neuronal nucleus remains unclear. In this work we present results concerning the interaction of tau protein with double-stranded DNA, single-stranded DNA, and also with a histone-DNA complex. The tau-DNA interaction results in a structure resembling the beads-on-a-string form produced by the binding of histone to DNA. DNA retardation assays show that tau and histone induce similar DNA retardation. A surface plasmon resonance study of tau-DNA interaction also confirms the minor groove of DNA as a …binding site for tau, similarly to the histone binding. A residual binding of tau to DNA in the presence of Distamycin A, a minor groove binder, suggests the possibility that additional structural domains on DNA may be involved in tau interaction. Finally, DNA melting experiments show that, according to the Zipper model of helix-coil transition, the binding of tau increases the possibility of opening the DNA double helix in isolated points along the chain, upon increasing temperature. This behavior is analogous to histones and supports the previously reported idea that tau could play a protective role in stress situations. Taken together, these results show a similar behavior of tau and histone concerning DNA binding, suggesting that post-translational modifications on tau might impair the role that, by modulating the DNA function, might be attributable to the DNA-tau interaction. Show more

Keywords: DNA, DNA melting, histones, surface plasmon resonance, tau protein, thermodynamics

DOI: 10.3233/JAD-131415

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 649-660, 2014

Authors: Moore, Eileen M. | Ames, David | Mander, Alastair G. | Carne, Ross P. | Brodaty, Henry | Woodward, Michael C. | Boundy, Karyn | Ellis, Kathryn A. | Bush, Ashley I. | Faux, Noel G. | Martins, Ralph N. | Masters, Colin L. | Rowe, Christopher C. | Szoeke, Cassandra | Watters, David A.

Article Type: Research Article

Abstract: Background: Folate fortification of food aims to reduce the number of babies born with neural tube defects, but has been associated with cognitive impairment when vitamin B12 levels are deficient. Given the prevalence of low vitamin B12 levels among the elderly, and the global deployment of food fortification programs, investigation of the associations between cognitive impairment, vitamin B12, and folate are needed. Objective: To investigate the associations of serum vitamin B12, red cell folate, and cognitive impairment. Methods: Data were collected on 1,354 subjects in two studies investigating cognitive impairment, and from patients attending for assessment …or management of memory problems in the Barwon region of south eastern Australia between 2001 and 2011. Eligible subjects who had blood measurements of vitamin B12 and red cell folate taken within six months of cognitive testing were included. Subjects with stroke or neurodegenerative diseases other than Alzheimer’s disease were excluded. A Mini-Mental State Examination score of <24 was used to define impaired cognitive function. Results: Participants with low serum vitamin B12 (<250 pmol/L) and high red cell folate (>1,594 nmol/L) levels were more likely to have impaired cognitive performance (adjusted odds ratio (AOR) 3.45, 95% confidence interval (CI): 1.60–7.43, p = 0.002) when compared to participants with biochemical measurements that were within the normal ranges. Participants with high folate levels, but normal serum vitamin B12, were also more likely to have impaired cognitive performance (AOR 1.74, 95% CI: 1.03–2.95, p = 0.04). Conclusions: High folate or folic acid supplements may be detrimental to cognition in older people with low vitamin B12 levels. This topic is of global significance due to the wide distribution of food fortification programs, so prospective studies should be a high priority. Show more

Keywords: Aged, Alzheimer's disease, cognition, folic acid, vitamin B12

DOI: 10.3233/JAD-131265

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 661-668, 2014

Authors: Perri, Roberta | Monaco, Marco | Fadda, Lucia | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Research Article

Abstract: The aim of this study was to investigate the neuropsychological correlates of behavioral and psychological symptoms (BPSD) in patients affected by various forms of dementia, namely Alzheimer's disease (AD), frontal-variant frontotemporal dementia (fvFTD), Lewy body dementia (LBD), and subcortical ischemic vascular dementia (SIVD). 21 fvFTD, 21 LBD, 22 AD, and 22 SIVD patients matched for dementia severity received a battery of neuropsychological tests and the Neuropsychiatry Inventory (NPI). The possible association between performance on neuropsychological tests and severity of BPSD was assessed by correlational analysis and multivariate regression. BPSD were present in 99% of patients. Most behavioral symptoms were not …related to a particular dementia group or to a specific cognitive deficit. Euphoria and disinhibition were predicted by fvFTD diagnosis. Hallucinations correlated with the severity of visuospatial deficits in the whole sample of patients and were predicted by LBD diagnosis. Apathy, which was found in all dementia groups, correlated with executive functions and was predicted by both reduced set-shifting aptitude and fvFTD diagnosis. The results confirm the high prevalence of BPSD in the mild to moderate stages of dementia and show that most BPSD are equally distributed across dementia groups. Most of the cognitive and behavioral symptoms are independent dimensions of the dementia syndromes. Nevertheless, hallucinations in LBD and euphoria and disinhibition in fvFTD are related to the structural brain alterations that are responsible for cognitive decline in these dementia groups. Finally, apathy arises from damage in the frontal cortical areas that are also involved in executive functions. Show more

Keywords: Alzheimer's disease, behavioral disorders, cognitive deficits, dementia with Lewy bodies, frontotemporal dementia, vascular dementia

DOI: 10.3233/JAD-131337

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 669-677, 2014

Authors: Paajanen, Teemu | Hänninen, Tuomo | Tunnard, Catherine | Hallikainen, Merja | Mecocci, Patrizia | Sobow, Tomasz | Tsolaki, Magda | Vellas, Bruno | Lovestone, Simon | Soininen, Hilkka | for the AddNeuroMed Consortium

Article Type: Research Article

Abstract: The Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) is a widely used tool in screening for Alzheimer's disease (AD), however, it does not include a validated total score for delayed memory. Our aim was to develop clinically applicable memory compound scores for CERAD-NB and examine whether they and global cognitive total scores could detect prodromal AD and cognitive progression in MCI. One year follow-up data of 201 subjects with a baseline diagnosis of MCI (46 progressed to AD; 155 remained stable) and 212 controls in the European multicenter AddNeuroMed study were analyzed. Two previously described cognitive …total scores and two memory compound scores were tabulated for CERAD-NB. Receiver Operating Characteristic analysis was applied in the group discrimination at baseline and the annual change for different compound scores was examined. Normative cut-offs for CERAD compound scores were tabulated in the Finnish CERAD sample of 306 controls. Country adjusted CERAD compound scores (AUC 0.95–0.96) were more accurate than Word List Recall (AUC 0.93) and Mini-Mental State Examination (AUC 0.90) in discriminating progressive mild cognitive impairment (MCI) subjects from controls. With normative cut-off values CERAD total scores yielded to 87–89% sensitivity and 84–86% specificity in screening for prodromal AD in a separate multinational population. The annual deterioration in all CERAD compound scores was significant in the progressive (p ≤ 0.001) but not in the stable MCI group (p > 0.08). CERAD total scores are a practical way of screening for prodromal AD and assessing cognitive progression in MCI. The new memory compound scores were more accurate than CERAD subtests in predicting AD conversion. Show more

Keywords: Alzheimer's disease, CERAD, cognition, memory, mild cognitive impairment, neuropsychology, prodromal Alzheimer's disease, screening dementia

DOI: 10.3233/JAD-122110

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 679-690, 2014

Authors: Brenowitz, Willa D. | Monsell, Sarah E. | Schmitt, Frederick A. | Kukull, Walter A. | Nelson, Peter T.

Article Type: Research Article

Abstract: Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (n = 9,817 participants), the neuropathological diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005–2012 (n = 1,422), additional analyses identified clinical and pathological features associated with …HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (n = 210). Reporting of HS-Aging pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively “pure” HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared with other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2–5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials. Show more

Keywords: APOE, hippocampus, human, oldest-old, TDP-43

DOI: 10.3233/JAD-131880

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 691-702, 2014