Journal of Alzheimer's Disease - Volume 54, issue 2

Authors: Fried, Itzhak

Article Type: Article Commentary

Abstract: Deep brain stimulation has been successfully used in treatment of motor symptoms of Parkinson’s disease and other movement disorders. In a recent multi-center prospectively randomized study, deep brain stimulation of the fornix was administered in order to ameliorate the cognitive symptoms and clinical course of Alzheimer’s disease (AD). The study points to the possibility of modest slowing of the cognitive decline in AD in a subset of patients older than 65, while at the same time highlights the risk of stimulation in exacerbation of this decline in younger patients. The logic of conducting large clinical trials in the face of …limited scientific understanding of the pathophysiology of AD and response of affected brain regions to electrical stimulation, is discussed with emphasis on the need to conduct: (i) animal studies in AD models, using precise focused stimulation; (ii) studies in patients who are implanted with depth electrodes for established clinical reasons (i.e., patients with epilepsy or movement disorders); and (iii) smaller adaptive studies in AD patients with systematic alterations of therapeutic parameters such as stimulation protocol. Show more

Keywords: Alzheimer’s disease, dementia, deep brain stimulation, fornix, hippocampus, entorhinal area

DOI: 10.3233/JAD-160719

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 789-791, 2016

Authors: Curiel, Rosie E. | Crocco, Elizabeth | Rosado, Marian | Duara, Ranjan | Greig, Maria T. | Raffo, Arlene | Loewenstein, David A.

Article Type: Research Article

Abstract: Background: Semantic memory interference has been found to be a predictive cognitive marker of incipient AD. This is relevant given that developing assessment paradigms to identify subtle cognitive and functional deficits is a priority in preclinical Alzheimer’s disease research. Objective: To examine the utility of a novel computerized paired associate test in distinguishing between mild cognitive impairment (MCI) and cognitively normal (CN) groups of older adults residing in the community. Methods: Participants that were CN (n  = 64) or MCI (n  = 34) were administered the Miami Test of Semantic Interference and Learning (MITSI-L). This novel instrument …is a brief, computerized paired associate test that measured the strength of memory binding of semantically related word pairs and introduced a proactive semantic interference condition which required participants to make different associations between semantically similar targets. A series of ANOVAs explored differences on MITSI-L performance. Logistic regression and receiver operator curves (ROC) analyses were employed to further determine discriminative validity. Results: MCI participants had lower scores on all indices relative to CN elders. A composite of two subscores correctly classified 85.3% of MCI and 84.4% of CN participants. Area under the ROC was higher relative to the MMSE, immediate memory for passages, and several subtests of a sensitive memory measure, the LASSI-L. Conclusions: The MITSI-L is a computerized test that can successfully differentiate MCI from CN participants. Area under the ROC curve exceeded that of global mental status and other memory measures. The effectiveness of the MITSI-L in detecting MCI, and its brief administration and portability render it worthy of further research. Show more

Keywords: Alzheimer’s disease, computerized tests, memory, mild cognitive impairment, MITSI-L

DOI: 10.3233/JAD-160370

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 793-799, 2016

Authors: Gomm, Willy | von Holt, Klaus | Thomé, Friederike | Broich, Karl | Maier, Wolfgang | Weckbecker, Klaus | Fink, Anne | Doblhammer, Gabriele | Haenisch, Britta

Article Type: Research Article

Abstract: Background: While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or BDZRs. For Germany, analyses on large population-based data sets are missing. Objective: To evaluate the association between regular BDZR use and incident any dementia in a large German claims data set. Methods: Using longitudinal German public health insurance data …from 2004 to 2011 we analyzed the association between regular BDZR use (versus no BDZR use) and incident dementia in a case-control design. We examined patient samples aged≥60 years that were free of dementia at baseline. To address potential protopathic bias we introduced a lag time between BDZR prescription and dementia diagnosis. Odds ratios were calculated applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy. Results: The regular use of BDZRs was associated with a significant increased risk of incident dementia for patients aged≥60 years (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13–1.29). The association was slightly stronger for long-acting substances than for short-acting ones. A trend for increased risk for dementia with higher exposure was observed. Conclusion: The restricted use of BDZRs may contribute to dementia prevention in the elderly. Show more

Keywords: Benzodiazepines, dementia, elderly, risk factor, z-substances

DOI: 10.3233/JAD-151006

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 801-808, 2016

Authors: Khmeleva, Svetlana A. | Radko, Sergey P. | Kozin, Sergey A. | Kiseleva, Yana Y. | Mezentsev, Yuri V. | Mitkevich, Vladimir A. | Kurbatov, Leonid K. | Ivanov, Alexis S. | Makarov, Alexander A.

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ) plays a central role in Alzheimer’s disease (AD) pathogenesis. Besides extracellular Aβ, intraneuronal Aβ (iAβ) has been suggested to contribute to AD onset and development. Based on reported in vitro Aβ-DNA interactions and nuclear localization of iAβ, the interference of iAβ with the normal DNA expression has recently been proposed as a plausible pathway by which Aβ can exert neurotoxicity. Employing the sedimentation assay, thioflavin T fluorescence, and dynamic light scattering we have studied effects of zinc ions on binding of RNA and single- and double-stranded DNA molecules to Aβ42 aggregates. It has been found …that zinc ions significantly enhance the binding of RNA and DNA molecules to pre-formed β-sheet rich Aβ42 aggregates. Another type of Aβ42 aggregates, the zinc-induced amorphous aggregates, was demonstrated to also bind all types of nucleic acids tested. To evaluate the role of the Aβ metal-binding domain’s histidine residues in Aβ-nucleic acid interactions mediated by zinc, Aβ16 mutants with substitutions H6R and H6A-H13A and rat Aβ16 lacking histidine residue 13 were used. The zinc-induced interaction of Aβ16 with DNA was shown to critically depend on histidine residues 6 and 13. However, the inclusion of H6R mutation in Aβ42 peptide did not affect DNA binding to Aβ42 aggregates. Since oxidative and/or nitrosative stresses implicated in AD pathogenesis are known to release zinc ions from metallothioneins in cytoplasm and cell nuclei, our findings suggest that intracellular zinc can be an important player in iAβ-nucleic acid interactions. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, DNA, histidine residues, RNA, zinc

DOI: 10.3233/JAD-160415

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 809-819, 2016

Authors: Selivanova, Olga M. | Surin, Alexey K. | Marchenkov, Victor V. | Dzhus, Ulyana F. | Grigorashvili, Elizaveta I. | Suvorina, Mariya Yu. | Glyakina, Anna V. | Dovidchenko, Nikita V. | Galzitskaya, Oxana V.

Article Type: Research Article

Abstract: It has been demonstrated using Aβ40 and Aβ42 recombinant and synthetic peptides that their fibrils are formed of complete oligomer ring structures. Such ring structures have a diameter of about 8-9 nm, an oligomer height of about 2– 4 nm, and an internal diameter of the ring of about 3-4 nm. Oligomers associate in a fibril in such a way that they interact with each other, overlapping slightly. There are differences in the packing of oligomers in fibrils of recombinant and synthetic Aβ peptides. The principal difference is in the degree of orderliness of ring-like oligomers that leads to generation of …morphologically different fibrils. Most ordered association of ring-like structured oligomers is observed for a recombinant Aβ40 peptide. Less ordered fibrils are observed with the synthetic Aβ42 peptide. Fragments of fibrils the most protected from the action of proteases have been determined by tandem mass spectrometry. It was shown that unlike Aβ40 , fibrils of Aβ42 are more protected, showing less ordered organization compared to that of Aβ40 fibrils. Thus, the mass spectrometry data agree with the electron microscopy data and structural models presented here. Show more

Keywords: Aβ42 and Aβ40 peptides, Alzheimer’s disease, amyloid fibrils, polymorphism, ring-like oligomers

DOI: 10.3233/JAD-160405

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 821-830, 2016

Authors: Zimova, Ivana | Brezovakova, Veronika | Hromadka, Tomas | Weisova, Petronela | Cubinkova, Veronika | Valachova, Bernadeta | Filipcik, Peter | Jadhav, Santosh | Smolek, Tomas | Novak, Michal | Zilka, Norbert

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151–391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting …of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy. Show more

Keywords: Alzheimer’s disease, neurofibrillary degeneration, tauopathies, transgenic mouse, truncated tau protein

DOI: 10.3233/JAD-160347

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 831-843, 2016

Authors: Cestari, José Augusto Ferrari | Fabri, Gisele Maria Campos | Kalil, Jorge | Nitrini, Ricardo | Jacob-Filho, Wilson | Tesseroli de Siqueira, José Tadeu | Siqueira, Silvia Regina D.T.

Article Type: Correction

DOI: 10.3233/JAD-169006

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 845-845, 2016

Article Type: Other

DOI: 10.3233/JAD-160728

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 847-852, 2016