Journal of Alzheimer's Disease - Volume 45, issue 3

Authors: Casamenti, Fiorella | Grossi, Cristina | Rigacci, Stefania | Pantano, Daniela | Luccarini, Ilaria | Stefani, Massimo

Article Type: Review Article

Abstract: The amyloid plaques and neurofibrillary tangles found in the Alzheimer's disease (AD) brain arise as a result of self-assembly into fibrillar material of amyloid-β protein (Aβ) and hyperphosphorylated tau, respectively, through a pathological process starting with the appearance of aggregation nuclei and neurotoxic oligomers. Accordingly, the search of inhibitors of oligomer nucleation and growth is considered a promising target to prevent amyloid toxicity. In recent years, a number of dietary factors including antioxidants, vitamins, and polyphenols have been characterized for their ability to protect cells stressed by several factors including the presence of amyloid deposits as well as to inhibit …amyloid self-assembly and cytotoxicity and some of them are currently in clinical trial. The present review summarizes the findings on the beneficial effects against neurodegeneration and other peripheral inflammatory and degenerative diseases of oleuropein aglycone (OLE), a natural phenol abundant in the extra virgin olive oil. The data presently available suggest that OLE could provide a protective and therapeutic effect against a number of pathologies, including AD as well as obesity, type 2 diabetes, non-alcoholic hepatitis, and other natural or experimentally-induced pathological conditions. Such a protection could result, at least in part, in a remarkable improvement of the pathological signs arising from stress conditions including oxidative stress, an excessive inflammatory response, and the presence of cytotoxic aggregated material. In particular, the recent data on the cellular and molecular correlates of OLE neuroprotection suggest it could also play a therapeutic role against AD. Show more

Keywords: Alzheimer's disease, amyloid-β deposits, autophagy, epigenetics, polyphenols, TgCRND8 mice

DOI: 10.3233/JAD-142850

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 679-688, 2015

Authors: Brommelhoff, Jessica A. | Sultzer, David L.

Article Type: Review Article

Abstract: The development of minimally invasive in vivo methods for imaging the brain has allowed for unprecedented advancement in our understanding of brain-behavior relationships. Structural, functional, and multimodal neuroimaging techniques have become more sophisticated in detecting structural and physiological abnormalities that may underlie various affective disorders and neurological illnesses such as depression in Alzheimer's disease (AD). In general, neuroimaging studies of depression in AD investigate whether depression is associated with damage to structures in specific neural networks involving frontal and subcortical structures or with functional disruption of cortical neural systems. This review provides an overview of how various imaging modalities have …contributed to our understanding of the neurobiology of depression in AD. At present, the literature does not conclusively support any specific pathogenesis for depression, and it is not clear whether patients with AD and depression have histopathological and neurochemical characteristics that contribute to mood symptoms that are different from cognitively intact individuals with depression. Neuroimaging studies suggest that atrophy of temporal or frontal structures, white matter lesions in frontal lobe or subcortical systems, reduced activity in dorsolateral frontal cortex, or small vessel cerebrovascular disease may be associated with depression in AD. Conceptual, clinical, and methodological challenges in studying this relationship are discussed. Further work is needed to understand the specific brain structures, relevant white matter tracts, and interactions among them that are most important. This review concludes with potential directions for future research. Show more

Keywords: Alzheimer's disease, depression, late-life depression, neuroimaging

DOI: 10.3233/JAD-148007

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 689-703, 2015

Authors: Leandri, Massimo | Campbell, Jackie | Molfetta, Luigi | Barbera, Cristina | Tabaton, Massimo

Article Type: Short Communication

Abstract: We investigated the relationship between balance and cognitive level in a group of 70 women with no definite Alzheimer's disease or mild cognitive impairment diagnosis and no impairment of daily activity. Static stabilometry and the Montreal Cognitive Assessment (MoCA) test were performed. The antero-posterior sway component was demonstrated to be the best predictor of the MoCA overall score. As visual and proprioceptive components of balance could safely be excluded in our assessments, the vestibular system is to be considered as a putative link between balance and cognitive impairment.

Keywords: Aging, cognitive performance, postural balance, vestibular system

DOI: 10.3233/JAD-142883

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 705-707, 2015

Authors: Pan, Catherine | Korff, Ané | Galasko, Douglas | Ginghina, Carmen | Peskind, Elaine | Li, Ge | Quinn, Joseph | Montine, Thomas J. | Cain, Kevin | Shi, Min | Zhang, Jing

Article Type: Research Article

Abstract: Background: Meso Scale Discovery (MSD) recently established electrochemiluminescence-based assays to measure cerebrospinal fluid (CSF) levels of total tau (t-tau) and amyloid-β 1-42 peptide (Aβ42 ) that can aid in the diagnosis of Alzheimer’s disease (AD). The goal of this investigation is to independently evaluate this platform and establish cut-off values of these biomarkers for AD diagnosis. Objective: To validate the analytical and clinical performance of the MSD t-tau and Aβ42 kits and propose diagnostic cut-off values for the field. Methods: The analytical performance of the CSF t-tau and Aβ42 assays was determined, followed by …assessment of diagnostic performance of CSF t-tau, Aβ42 , and t-tau/Aβ42 in three clinically characterized cohorts. Results: Both MSD assays demonstrated consistent and stable analytical performance, as well as resistance to several important pre-analytic variables. Diagnostically, t-tau/Aβ42 performed the best. Conclusions: Our results independently confirm the analytical and clinical performance of the MSD CSF t-tau and Aβ42 assays. Based on a large, multi-center, clinically-diagnosed cohort, we propose for the first time candidate diagnostic cut-offs for MSD measured CSF t-tau, Aβ42 , and t-tau/Aβ42 . However, these values needs to be refined as more subjects are included and the assays are tested by other laboratories. Show more

Keywords: Aβ42, Alzheimer's disease, cerebrospinal fluid, Meso Scale Discovery, tau

DOI: 10.3233/JAD-143099

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 709-719, 2015

Authors: Xie, Bing | Zhou, Huimin | Zhang, Rui | Song, Mei | Yu, Lulu | Wang, Lan | Liu, Zanchao | Zhang, Qingfu | Cui, Dongsheng | Wang, Xueyi | Xu, Shunjiang

Article Type: Research Article

Abstract: MicroRNAs (miRNAs), a class of small, non-coding RNA molecules with gene regulatory functions, have emerged to play a critical role in the pathogenesis of a variety of diseases. Recently, circulating miRNAs have been reported as potential biomarkers for various pathologic conditions. The present study was performed to investigate the potential role of circulating miRNAs as diagnostic biomarkers for mild cognitive impairment (MCI). We collected 66 patients with MCI and 76 normal controls from our previous cross-sectional cohort study. Seven miRNAs (miR-206, miR-132, miR-193b, miR-130b, miR-20a, miR-296, and miR-329) related to Alzheimer's disease (AD) were detected in serum using a quantitative …real-time PCR (qRT-PCR) method. Each miRNA's diagnostic performance was evaluated by receiver operating characteristic curves and the areas under curves (AUC) analysis. The levels of miR-206 and miR-132 in MCI patients' serum were significantly elevated compared to normal controls. Combining detection of miR-206 and miR-132 achieved the highest AUC of 0.981, followed by test of miR-206 (AUC = 0.880) and miR-132 (AUC = 0.912) separately. Importantly, miR-206 and miR-132 were respectively correlated with the Montreal Cognitive Assessment score in MCI patients. These results preliminarily indicated that circulating miR-206 and miR-132 as novel miRNAs upregulated in MCI patient were potential biomarkers for diagnosis of MCI. Show more

Keywords: Biomarkers, diagnosis, microRNA, mild cognitive impairment, serum

DOI: 10.3233/JAD-142847

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 721-731, 2015

Authors: Naudé, Petrus J.W. | Dekker, Alain D. | Coppus, Antonia M.W. | Vermeiren, Yannick | Eisel, Ulrich L.M. | van Duijn, Cornelia M. | Van Dam, Debby | De Deyn, Peter P.

Article Type: Research Article

Abstract: Background: The majority of people with Down syndrome (DS) develop dementia due to Alzheimer’s disease (AD). Neuropathological features are characterized by an accumulation of amyloid-β (Aβ) deposits and the presence of an activated immune response. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a newly identified (neuro)inflammatory constituent in AD. Objective: This study examines NGAL as an inflammatory marker in DS and its associations with plasma Aβ peptides according to the follow-up clinical diagnosis of dementia. Methods: Baseline serum NGAL and plasma Aβ40 , Aβ42 , Aβn40 , and Aβn42 were quantified in 204 people with DS. The …diagnosis of dementia in DS was established by follow-up clinical assessments. The following study groups were characterized: DS with AD at baseline (n = 67), DS without AD (n = 53), and non-demented DS individuals that converted to AD (n = 84). Serum NGAL was analyzed in 55 elderly non-DS, non-demented people. Results: Serum NGAL levels were significantly increased in DS subjects compared to non-DS people. Serum NGAL levels were not associated with clinical dementia symptoms in DS. However, NGAL was positively associated with Aβ42 and Aβn42 in demented DS individuals and with Aβ40 and Aβn40 in the non-demented DS group. NGAL was negatively associated with Aβ42 /Aβ40 and Aβn42 /Aβn40 ratios in converted DS subjects. These associations persisted for Aβn40 , Aβ42 /Aβ40 , and Aβn42 /Aβn40 after adjusting for demographics measures, apolipoprotein E ε4 allele, platelets, and anti-inflammatory medication. Conclusion: Serum NGAL levels are increased in DS and associated with distinct species of Aβ depending on the progression of dementia as diagnosed by baseline and follow-up clinical assessments. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E, biomarker, down syndrome, inflammation, lipocalin 2, platelets

DOI: 10.3233/JAD-142514

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 733-743, 2015

Authors: Vecchio, Fabrizio | Miraglia, Francesca | Curcio, Giuseppe | Altavilla, Riccardo | Scrascia, Federica | Giambattistelli, Federica | Quattrocchi, Carlo Cosimo | Bramanti, Placido | Vernieri, Fabrizio | Rossini, Paolo Maria

Article Type: Research Article

Abstract: A relatively new approach to brain function in neuroscience is the “functional connectivity”, namely the synchrony in time of activity in anatomically-distinct but functionally-collaborating brain regions. On the other hand, diffusion tensor imaging (DTI) is a recently developed magnetic resonance imaging (MRI)-based technique with the capability to detect brain structural connection with fractional anisotropy (FA) identification. FA decrease has been observed in the corpus callosum of subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI, an AD prodromal stage). Corpus callosum splenium DTI abnormalities are thought to be associated with functional disconnections among cortical areas. This study aimed to …investigate possible correlations between structural damage, measured by MRI-DTI, and functional abnormalities of brain integration, measured by characteristic path length detected in resting state EEG source activity (40 participants: 9 healthy controls, 10 MCI, 10 mild AD, 11 moderate AD). For each subject, undirected and weighted brain network was built to evaluate graph core measures. eLORETA lagged linear connectivity values were used as weight of the edges of the network. Results showed that callosal FA reduction is associated to a loss of brain interhemispheric functional connectivity characterized by increased delta and decreased alpha path length. These findings suggest that “global” (average network shortest path length representing an index of how efficient is the information transfer between two parts of the network) functional measure can reflect the reduction of fiber connecting the two hemispheres as revealed by DTI analysis and also anticipate in time this structural loss. Show more

Keywords: Alzheimer's disease, delta and alpha bands, diffusion tensor imaging, EEG, functional connectivity, graph theory, mild cognitive impairment, sLORETA/eLORETA

DOI: 10.3233/JAD-142484

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 745-756, 2015

Authors: Calderón-Garcidueñas, Lilian | Mora-Tiscareño, Antonieta | Franco-Lira, Maricela | Zhu, Hongtu | Lu, Zhaohua | Solorio, Edelmira | Torres-Jardón, Ricardo | D'Angiulli, Amedeo

Article Type: Research Article

Abstract: Children's urban air pollution exposures result in systemic and brain inflammation and the early hallmarks of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most prevalent genetic risk for AD. We assessed whether APOE in healthy children modulates cognition, olfaction, and metabolic brain indices. The Wechsler Intelligence Scale for Children (WISC-R) and the University of Pennsylvania Smell Identification Test were administered to 50 Mexico City Metropolitan Area children (13.4 ± 4.8 years, 28 APOE ε3 and 22 APOE ε4). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (mI)/Cr, and NAA/mI were calculated using proton magnetic resonance spectroscopy in the …white matter of the frontal and parietal lobes, hippocampus, and pons. APOE ε4 versus ε3 children had a reduced NAA/Cr ratio in the right frontal white matter and decrements on attention, short-term memory, and below-average scores in Verbal and Full Scale IQ (>10 points). APOE modulated the group effects between WISC-R and left frontal and parietal white matter, and hippocampus metabolites. Soap was the predominantly failed odor in urban children and, in APOE ε4 versus ε3 carriers, strongly correlated with left hippocampus mI/Cr ratio. APOE modulates responses to air pollution in the developing brain. APOE ε4 carriers could have a higher risk of developing early AD if they reside in a polluted environment. APOE, cognition, and olfaction testing and targeted magnetic resonance spectroscopy may contribute to the assessment of urban children and their results could provide new paths toward the unprecedented opportunity for early neuroprotection and AD prevention. Show more

Keywords: Air pollution, APOE, children, cognition, frontal white matter, hippocampus, olfaction, magnetic resonance spectroscopy, megacities, neuroprotection, particulate matter

DOI: 10.3233/JAD-142685

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 757-770, 2015

Authors: Matsuzono, Kosuke | Hishikawa, Nozomi | Ohta, Yasuyuki | Yamashita, Toru | Deguchi, Kentaro | Nakano, Yumiko | Abe, Koji

Article Type: Research Article

Abstract: Background/Objective: To compare the effectiveness of combination therapy with cholinesterase inhibitors (ChEI) plus memantine in all AD patients and in older AD patients (age >75 years). Methods: The Okayama Memantine Study was used to compare the clinical effects of combination therapy of donepezil plus memantine (n = 61) or galantamine plus memantine (n = 53) in all AD patients, and in older AD patients separately, with six batteries at baseline, at 6 months with ChEI only monotherapy, and at 3, 6, and 12 months after addition of memantine to the treatment schedule (18 months total). Results: …The addition of memantine resulted in stabilization of the Mini-Mental State Examination scores and Hasegawa dementia rating for 6 months, and then significantly declined at 12 months in both subgroups. Frontal assessment battery (FAB) declined significantly at 12 months after memantine addition in the donepezil subgroup, while the galantamine subgroup significantly improved at 6 months. Affective functions were well preserved after memantine addition until 12 months, except for the apathy scale at 12 months after memantine addition in the galantamine subgroup. The combination therapy of donepezil plus memantine was better for apathy in older AD patients, and galantamine plus memantine was better for cognitive functions. Conclusions: The addition of memantine stabilized cognitive scores for 6 months and affective scores for 12 months in the donepezil subgroup. Additionally, memantine significantly improved FAB at 6 months in the galantamine subgroup although apathy scale became significantly worse at 12 months. Show more

Keywords: Alzheimer's disease, combination therapy, donepezil, galantamine, memantine

DOI: 10.3233/JAD-143084

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 771-780, 2015

Authors: Wang, Xiao | Wang, Jinhui | He, Yi | Li, Huiying | Yuan, Huishu | Evans, Alan | Yu, Xin | He, Yong | Wang, Huali

Article Type: Research Article

Abstract: The apolipoprotein E ε4 (APOE ε4) allele is a well-established genetic risk factor for Alzheimer's disease (AD). Numerous studies have suggested that the modulation of APOE ε4 affects cognition and brain structure and function in healthy populations, particularly in the hippocampus, a key area associated with AD pathology. However, the effect of APOE ε4 allele on cognitive performance, hippocampal structural morphology, and specifically on functional characteristics in patients with AD remains poorly understood. Here, we employed a neuropsychological battery test and multi-modal structural MRI and resting-state functional MRI dataset to systematically investigate cognitive performance, hippocampal structural volume, and functional properties …(including local low-frequency oscillating amplitude, intra-regional functional synchrony, and inter-regional functional connectivity) in 16 APOE ε4-carriers and 26 non-carriers at early stages of AD. Compared to non-carriers, APOE ε4-carriers exhibited poorer performance on recognition performance, but performed better on the late item generation of the verbal fluency task (associated with executive function). Structural imaging analysis revealed that APOE ε4-carriers exhibited smaller left hippocampal volumes compared to non-carriers, and the result remains significant after correcting for effects of brain size. Functional imaging analysis revealed that APOE ε4-carriers exhibited decreased amplitude of low-frequency fluctuations in the left hippocampus, non-significant changes in intra-regional synchronization within the hippocampus and decreased hippocampal functional connectivity predominantly in components of the default-mode network including the medial frontal and parietal cortices and the lateral temporal cortical regions. Taken together, our results showed APOE genotypic effects on the cognitive profile and hippocampal structural and functional characteristics in patients at early stages of AD, thus providing empirical evidence for the modulation of the APOE genotype on disease phenotype. Show more

Keywords: Apolipoprotein E, default-mode, functional connectivity, hippocampus, resting-state functional MRI

DOI: 10.3233/JAD-142556

Citation: Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 781-795, 2015