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

Authors: Kasahata, Naoki | Hagiwara, Mariko | Kato, Hiroyuki | Nakamura, Ayako | Uchihara, Toshiki

Article Type: Short Communication

Abstract: An 85-year-old man developed l-dopa responsive parkinsonism indistinguishable from Parkinson's disease and subsequent dementia, followed by supranuclear ophthalmoplegia and neck dorsiflexion at the terminal stage. Midbrain tegmentum and medial temporal lobe were atrophic on magnetic resonance imaging, while decreased blood flow was predominant in frontotemporal lobes, detected by 3D-SSP of 123I- IMP SPECT. Alzheimer-type pathology without Lewy body pathology was confirmed at autopsy. Substantia nigra showed mild degeneration and several neurofibrillary tangles without Lewy body pathology or progressive supranuclear palsy cytopathology. L-dopa responsive parkinsonism could be an initial manifestation of Alzheimer's disease, which should be included in the differential diagnosis.

Keywords: Alzheimer's disease, 3-iodobenzylguanidine, levodopa, Lewy bodies, Parkinsonian disorders, progressive supranuclear palsy, Tegmentum mesencephali

DOI: 10.3233/JAD-131508

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 471-476, 2014

Authors: Cumbo, Eduardo | Ligori, Leonarda Domenica

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) occur in up to 80% of Alzheimer’s disease (AD) patients and represent one of the most common reasons for early institutionalization and increase in management costs. Objectives: This study evaluated the effects of four drugs (memantine, donepezil, rivastigmine, galantamine) in BPSD in AD patients. Methods: This was a prospective, longitudinal, randomized, open-label, 4-arm, parallel-group, 12-month clinical trial carried out in 177 AD patients. The severity of BPSD was evaluated at baseline and after treatment with memantine (n = 48), donepezil (n = 42), rivastigmine (n = 46), and …galantamine (n = 41), by using the Neuropsychiatric Inventory (NPI) and the Behavioural Pathology in Alzheimer’s Disease (BEHAVE-AD) scales. Results: The NPI and BEHAVE-AD total scores improved from baseline to month 12 in all groups. The improvements in both scales were statistically significant in the memantine, donepezil, and rivastigmine groups, but not in the galantamine group. Responder analyses showed that treatment with memantine and rivastigmine resulted in more patients improving on NPI and BEHAVE-AD score, respectively. Agitation/aggression was the NPI item with the highest improvements (significantly versus baseline in the memantine and in the rivastigmine groups), while aggression and anxiety/phobias were the mostly improved BEHAVE-AD items (significantly in the rivastigmine group for both and in the rivastigmine group only for anxiety/phobias). All treatments were well tolerated: most of adverse events reported were transient and of mild-to-moderate intensity. Conclusions: This study suggests that specific drugs for AD, especially memantine and rivastigmine, may be effective in the improvement of BPSD in patients with mild to moderate AD, without major side effects. Show more

Keywords: Alzheimer's disease, behavioral and psychological symptoms, donepezil, galantamine, memantine, rivastigmine

DOI: 10.3233/JAD-131190

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 477-485, 2014

Authors: Schwenk, Michael | Dutzi, Ilona | Englert, Stefan | Micol, William | Najafi, Bijan | Mohler, Jane | Hauer, Klaus

Article Type: Research Article

Abstract: Background: Translation of intensive exercise programs developed specifically for patients with dementia into clinical settings is lacking. Objective: To determine if a progressive resistance and functional training program, previously evaluated in dementia outpatients, can be implemented in a geriatric inpatient setting in order to improve motor performances in patients with dementia. Methods: Eligible patients in one ward of a German geriatric hospital were assigned to the intervention group (IG, n = 74) and received intensive exercise training specifically designed for patients with dementia. Patients in the second ward were observed as a control group (CG, n …= 74). All patients received usual care treatment. Primary endpoints were maximal lower extremity strength measured by a leg-press device and duration of the 5-chair-stand test for functional performance. Secondary outcomes included a number of parameters for strength and function. Results: The rehabilitation period averaged 18.1 ± 6.8 days. The IG significantly improved in both primary endpoints (change: maximal strength, IG: +51.9 ± 42.3% versus CG: +13.5 ± 51.8%, p < 0.001; functional performance, IG: −19.2 ± 22.3% versus CG: −3.8 ± 32.2% s, p = 0.037). Secondary outcomes confirmed effects for strength and some, but not all, functional parameters. Interestingly, low baseline motor status, but not cognitive status, predicted positive training response. Conclusion: An intensive exercise program can be implemented in a geriatric rehabilitation setting to improve motor performances in patients with dementia. Results suggest that an intensification of training is feasible in the target group and substantially increases the benefits in comparison to receiving usual care exercise only. Show more

Keywords: Cognitive impairment, dementia, exercise, geriatrics, rehabilitation, resistance training

DOI: 10.3233/JAD-130470

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 487-498, 2014

Authors: Perrin, Paul B. | Morgan, Matthew | Aretouli, Eleni | Sutter, Megan | Snipes, Daniel J. | Hoyos, Guillermo Ramirez | Buraye, Jacqueline Arabia | Arango-Lasprilla, Juan Carlos

Article Type: Research Article

Abstract: Research in Caucasian populations has begun to examine the broad associations between physical and mental health in dementia caregivers. However, the examination of this relationship in Latin America is largely absent from the literature despite the fact that the region will see a major increase in dementia cases over the next 20 years. The current study examined the associations between health-related quality of life (HRQOL) and mental health in 90 dementia caregivers from Colombia, South America. A canonical correlation found that higher caregiver HRQOL was related to better mental health, as expected. Caregivers with high vitality and low role limitations …due to physical problems tended to have low depression and high satisfaction with life. Follow-up multiple regressions found that caregiver role limitations due to physical problems was uniquely associated with satisfaction with life, whereas vitality, role limitations due to physical problems, and pain were uniquely associated with burden (although the pain effect was likely error due to a suppressor effect). Additionally, vitality and social functioning were uniquely negatively related to depression. Because of the extremely high overlap between these two sets of variables, dementia interventions are needed in Latin America that target both caregiver mental and physical health, as both likely operate in unison and influence each other. Show more

Keywords: Dementia caregivers, health related quality of life, Latin America, mental health

DOI: 10.3233/JAD-130764

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 499-509, 2014

Authors: Conde-Sala, Josep L. | Turró-Garriga, Oriol | Garre-Olmo, Josep | Vilalta-Franch, Joan | Lopez-Pousa, Secundino

Article Type: Research Article

Abstract: Cross-sectional studies report notable discrepancies between patient and caregiver ratings of the quality of life of patients (QoL-p) with Alzheimer's disease (AD). This study aimed to identify the factors associated with any changes in QoL-p ratings and any discrepancies between patient and caregiver ratings of QoL-p. Three-year follow-up of a cohort of non-institutionalized patients (n = 119). QoL-p was assessed by the Quality of Life in AD (QoL-AD) scale. We analyzed the influence of functional and cognitive status and behavioral problems in patients, and burden and mental health in caregivers. Repeated measures analysis was applied to the scores of patients …and caregivers on the QoL-AD, and to the discrepancies between them. Generally, patients' own ratings remained stable over time (F3,116 = 0.9, p = 0.439), whereas caregiver ratings showed a decline (F3,116 = 9.4, p < 0.001). In the analysis of discrepancies, patients with anosognosia gave higher ratings (F1,117 = 11.9, p = 0.001), whereas caregiver ratings were lower when the patient showed greater agitation (F1,117 = 13.0, p < 0.001), apathy (F1,117 = 15.4, p < 0.001), and disabilities (F1,117 = 17.1, p < 0.001), and when the caregiver experienced greater burden (F1,117 = 9.0, p = 0.003) and worse mental health (F1,117 = 10.1, p = 0.003). Patient ratings of QoL-p remain generally stable over time, whereas those of caregivers show a decline, there being significant discrepancies in relation to specific patient and caregiver factors. Show more

Keywords: Alzheimer's disease, anosognosia, caregiver burden, caregivers, disabilities, longitudinal study, mental health, neuropsychiatric symptoms, patients, quality of life

DOI: 10.3233/JAD-131286

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 511-525, 2014

Authors: Xia, Mingrui | Wang, Zhiqun | Dai, Zhengjia | Liang, Xia | Song, Haiqing | Shu, Ni | Li, Kuncheng | He, Yong

Article Type: Research Article

Abstract: Neuroimaging studies have demonstrated that patients with Alzheimer's disease (AD) have remarkable focal grey matter loss and hypometabolism in the posteromedial cortex (PMC), which is composed of the precuneus and posterior cingulate cortex, suggesting an important association of the PMC with AD pathophysiology. Studies have also shown that the PMC is a structurally and functionally heterogeneous structure containing various subregions with distinct connectivity profiles. However, whether these PMC subregions show differentially disrupted connectivity patterns in AD remains largely unknown. Here, we addressed this issue by collecting resting-state functional MRI data from 32 AD patients and 38 healthy controls. We automatically …identified the PMC subregions using a graph-based module detection algorithm and then mapped the whole-brain functional connectivity pattern of each subregion. The functional connectivity analysis was followed by a hierarchical clustering analysis to classify each subregion. Three distinct spatial connectivity patterns were observed across the PMC subregions: the anterior dorsal zone was functionally connected with the sensorimotor cortex; the posterior dorsal zone was functionally connected with the frontoparietal cortex; and the central and ventral zones were functionally connected with the default-mode regions. Group comparison analysis revealed that all three functional systems were significantly disrupted in the AD patients compared to the controls and these disruptions were positively correlated with the patients' cognitive performance. Collectively, we showed that the subregions of the PMC exhibit differentially disrupted neuronal circuitry in AD patients, which provides new insight into the functional neuroanatomy of the human PMC and the alterations that may be relevant to disease. Show more

Keywords: Alzheimer's disease, connectome, dementia, functional magnetic resonance imaging, network, parietal lobe

DOI: 10.3233/JAD-131583

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 527-543, 2014

Authors: Kanyenda, Limbikani J. | Verdile, Guiseppe | Martins, Ralph | Meloni, Bruno P. | Chieng, Joanne | Mastaglia, Francis | Laws, Simon M. | Anderton, Ryan S. | Boulos, Sherif

Article Type: Research Article

Abstract: The CD147 protein is a ubiquitous multifunctional membrane receptor. Expression of CD147, which is regulated by sterol carrier protein, reportedly modulates amyloid-β (Aβ), the neurotoxic peptide implicated in neuronal degeneration in Alzheimer's disease (AD). Given that high fat/cholesterol is linked to amyloid deposition in AD, we investigated if cholesterol and/or Aβ can alter CD147 expression in rat cortical neuronal cultures. Water-soluble cholesterol and Aβ42 dose-dependently increased CD147 protein expression, but reduced FL-AβPP protein expression. Cholesterol and Aβ42 treatment also increased lactate dehydrogenase release but to varying degrees. Upregulation of CD147 expression was probably mediated by oxidative stress, as …H2 O2 (3 μM) also induced CD147 protein expression in neuronal cultures. In light of these findings, we investigated if CD147 induction was cytoprotective, a compensatory response to injury, or alternatively, a cell death signal. To this end, we used recombinant adenovirus to overexpress human CD147 (in SH-SY5Y cells and primary cortical neurons), and pre-treated cultures with or without recombinant cyclophilin A (rCYPA) protein, prior to Aβ42 exposure. We showed that increased CD147 expression protected against Aβ42 , only when rCYPA protein was added to neuronal cultures. Together, our findings reveal potentially important relationships between cholesterol loading, CD147 expression, Aβ toxicity, and the putative involvement of CYPA protein in neuroprotection in AD. Show more

Keywords: Aβ42, Alzheimer's disease, CD147, cholesterol, cyclophilin A, neuroprotection

DOI: 10.3233/JAD-131442

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 545-556, 2014

Authors: Tzikas, Stergios | Schlak, Dennis | Sopova, Kateryna | Gatsiou, Aikaterini | Stakos, Dimitrios | Stamatelopoulos, Kimon | Stellos, Konstantinos | Laske, Christoph

Article Type: Research Article

Abstract: Background: Increasing evidence supports the role of cardiovascular risk factors in the development of Alzheimer’s disease (AD). Objective: In the present pilot study, we investigated plasma concentrations of myeloperoxidase (MPO) and its possible association with plasma amyloid-β (Aβ)1-42/1-40 ratio in AD patients and elderly healthy controls. Methods: The study sample included 28 AD patients and 27 elderly individuals with a normal cognitive status as a control group. The Mini-Mental Status Examination was used to determine the global cognition. MPO, Aβ1-40 , and Aβ1-42 plasma concentrations were measured by enzyme linked immunoabsorbent assays. …Results: AD patients showed significantly higher plasma concentrations of MPO in comparison to healthy elderly controls (AD versus healthy elderly controls (mean ± SD): 132.8 ± 114.8 ng/mL versus 55.0 ± 42.6 ng/mL; p = 0.002). MPO plasma concentrations showed a significant positive correlation in the whole sample with the presence of AD (ρ = 0.428, p < 0.001) and its stage (ρ = 0.331; p = 0.013) as well as with plasma concentrations of Aβ1-42 (ρ = 0.406; p = 0.004) and Aβ1-42/1-40 ratio (ρ = 0.354; p = 0.013). In a binary logistic regression model, plasma MPO concentrations were independently associated with the presence of AD (p = 0.014). Conclusion: AD patients showed significantly increased plasma levels of MPO, which could be an important molecular link between atherosclerosis and AD. Further studies should evaluate whether MPO may also be a useful biomarker and potential new treatment target in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, dementia, myeloperoxidase

DOI: 10.3233/JAD-131469

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 557-564, 2014

Authors: Harris, Sarah E. | Davies, Gail | Luciano, Michelle | Payton, Antony | Fox, Helen C. | Haggarty, Paul | Ollier, William | Horan, Michael | Porteous, David J. | the Genetic and Environmental Risk for Alzheimer's disease (GERAD1) Consortium | Starr, John M. | Whalley, Lawrence J. | Pendleton, Neil | Deary, Ian J.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) and non-pathological cognitive aging have phenotypic similarities which may be influenced by an overlapping set of genetic variants. Genome-wide complex trait analysis estimates that common genetic variants account for about 24% of the variation contributing to liability for AD. It is also estimated that 24% of the variance of non-pathological cognitive aging is accounted for by common single nucleotide polymorphisms. However, although the APOE locus is associated with both AD and cognitive aging, it is not known to what extent other common genetic variants, with smaller effect sizes that influence both, overlap. We test the hypothesis that …polygenic risk for AD is associated with cognitive ability and cognitive change in about 3,000 non-demented older people (Cognitive Ageing Genetics England and Scotland-CAGES-consortium). We found no significant association of polygenic risk for AD with cognitive ability or cognitive change in CAGES, indicating that the genetic etiologies of AD and non-pathological cognitive decline differ. Show more

Keywords: Aging, Alzheimer's disease, cognition, cohort studies, genetics, polygenic traits

DOI: 10.3233/JAD-131058

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 565-574, 2014

Authors: Lyness, Scott A. | Lee, Ae Young | Zarow, Chris | Teng, Evelyn L. | Chui, Helena C.

Article Type: Research Article

Abstract: We compared the sensitivity and specificity of two delayed recall scores from the Modified Mini-Mental State (3MS) test with consensus clinical diagnosis to differentiate cognitive impairment due to Alzheimer's disease (AD) versus non-AD pathologies. At a memory disorders clinic, 117 cognitively impaired patients were administered a baseline 3MS test and received a contemporaneous consensus clinical diagnosis. Their brains were examined after death about 5 years later. Using logistic regression with forward selection to predict pathologically defined AD versus non-AD, 10-min delayed recall entered first (p = 0.001), followed by clinical diagnosis (p = 0.02); 1-min delayed recall did not enter. …10-min delayed recall scores ≤4 (score range = 0–9) were 87% sensitive and 47% specific in predicting AD pathology; consensus clinical diagnosis was 82% sensitive and 45% specific. For the 57 patients whose initial Mini-Mental State Examination scores were ≥19 (the median), 3MS 10-min delayed recall scores ≤4 showed some loss of sensitivity (80%) but a substantial gain in specificity (77%). In conclusion, 10-min delayed recall score on the brief 3MS test distinguished between AD versus non-AD pathology about 5 years before death at least as well as consensus clinical diagnosis that requires much more comprehensive information and complex deliberation. Show more

Keywords: Autopsy, consensus, dementia, memory disorders, Modified Mini-Mental State (3MS), neuropsychological tests, sensitivity and specificity

DOI: 10.3233/JAD-130524

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 575-582, 2014

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

Article Type: Other

DOI: 10.3233/JAD-131881

Citation: Journal of Alzheimer's Disease, vol. 39, no. 3, pp. 703-705, 2014