Journal of Alzheimer's Disease - Volume 48, issue 3

Authors: Karnati, Hanuma Kumar | Panigrahi, Manas Kumar | Gutti, Ravi Kumar | Greig, Nigel H. | Tamargo, Ian A.

Article Type: Review Article

Abstract: MicroRNAs (miRNAs) are endogenous, ∼22 nucleotide, non-coding RNA molecules that function as post-transcriptional regulators of gene expression. miRNA dysregulation has been observed in cancer and in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis, and the neurological disorder, epilepsy. Neuronal degradation and death are important hallmarks of neurodegenerative disorders. Additionally, abnormalities in metabolism, synapsis and axonal transport have been associated with Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. A number of recently published studies have demonstrated the importance of miRNAs in the nervous system and have contributed to the growing body of evidence on miRNA dysregulation …in neurological disorders. Knowledge of the expressions and activities of such miRNAs may aid in the development of novel therapeutics. In this review, we discuss the significance of miRNA dysregulation in the development of neurodegenerative disorders and the use of miRNAs as targets for therapeutic intervention. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, epilepsy, Huntington’s disease, miRNAs, neurodegenerative disorders, Parkinson’s disease

DOI: 10.3233/JAD-150395

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 563-580, 2015

Authors: Menéndez-González, Manuel | de Celis Alonso, Benito | Salas-Pacheco, José | Arias-Carrión, Oscar

Article Type: Review Article

Abstract: Atrophy in the medial temporal lobe (MTA) is being used as a criterion to support a diagnosis of Alzheimer’s disease (AD). There are several structural neuroimaging approaches for quantifying MTA, including semiquantitative visual rating scales, volumetry (3D), planimetry (2D), and linear measures (1D). Current applications of structural neuroimaging in Alzheimer’s disease clinical trials (ADCTs) incorporate it as a tool for improving the selection of subjects for enrollment or for stratification, for tracking disease progression, or providing evidence of target engagement for new therapeutic agents. It may also be used as a surrogate marker, providing evidence of disease-modifying effects. However, despite …the widespread use of volumetric magnetic resonance imaging (MRI) in ADCTs, there are some important challenges and limitations, such as difficulties in the interpretation of results, limitations in translating results into clinical practice, and reproducibility issues, among others. Solutions to these issues may arise from other methodologies that are able to link the results of volumetric MRI from trials with conventional MRIs performed in routine clinical practice (linear or planimetric methods). Also of potential benefit are automated volumetry, using indices for comparing the relative rate of atrophy of different regions instead of absolute rates of atrophy, and combining structural neuroimaging with other biomarkers. In this review, authors present the existing structural neuroimaging approaches for MTA quantification. They then discuss solutions to the limitations of the different techniques as well as the current challenges of the field. Finally, they discuss how the current advances in AD neuroimaging can help AD diagnosis. Show more

Keywords: Alzheimer’s disease, clinical trail, neuroimaging, structural

DOI: 10.3233/JAD-150226

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 581-589, 2015

Authors: Remington, Ruth | Lortie, Jevin J. | Hoffmann, Heather | Page, Robert | Morrell, Christopher | Shea, Thomas B.

Article Type: Short Communication

Abstract: Thirty-four individuals with mild cognitive impairment were randomized for 6 months to a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or indistinguishable placebo, followed by a 6-month open-label extension in which all individuals received NF. The NF cohort improved in the Dementia Rating Scale (DRS; effect size >0.7) and maintained baseline performance in CLOX-1. The placebo cohort did not improve in DRS and declined in CLOX-1, but during the open-label extension improved in DRS and ceased declining in CLOX-1. These findings extend prior studies of NF efficacy for individuals without cognitive impairment and with Alzheimer’s disease.

Keywords: Aging, Alzheimer’s disease, cognitive performance, dementia, mild cognitive impairment, nutraceutical

DOI: 10.3233/JAD-150057

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 591-595, 2015

Authors: Popova, Svetlana N. | Pesälä, Samuli | Alafuzoff, Irina

Article Type: Short Communication

Abstract: For Braak staging of Alzheimer’s disease (AD), the assessment of only hippocampal section has been proposed. In two published modifications, the emphasis is on the pathology in Ammon’s horn. We investigated this approach in a cohort including 150 cases. A Braak stage was possible to assign in a subset of the cases, and the agreement rates varied from 60% to 36% . Thus, to reliably stage the AD-related neurodegeneration, regions such as the entorhinal, transentorhinal, temporo-occipital, and occipital cortices should be assessed as has also been recommended in 2012 by the National Institute on Aging - Alzheimer’s Association guidelines.

Keywords: Alzheimer’s disease, ammon’s horn, braak stage, hippocampus

DOI: 10.3233/JAD-150494

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 597-601, 2015

Authors: Guo, Zhongwei | Liu, Xiaozheng | Jia, Xize | Hou, Hongtao | Cao, Yulin | Wei, Fuquan | Li, Jiapeng | Chen, Xingli | Zhang, Yingchun | Shen, Yuedi | Wei, Lili | Xu, Luoyi | Chen, Wei

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive cognitive decline along with neuropsychiatric symptoms including depression and psychosis. Depression is a common psychiatric disorder occurring in people across the lifespan. Accumulating evidence indicates that depression may be a prodrome and/or a “risk factor” for AD. However, whether AD and depression share a common pathophysiological pathway is still unclear. The aim of this study was to identify regional alterations in brain function associated with depressive symptoms in mild AD patients. Thirty-two mild AD patients were evaluated using the Neuropsychiatric Inventory and Hamilton Depression Rating Scale, and were divided into two groups: 15 …AD patients with depressive symptoms (D-AD) and 17 non-depressed AD (nD-AD) patients. Using the approach of regional homogeneity (ReHo), we characterized resting-state regional brain activity in D-AD and nD-AD patients. Compared with nD-AD patients, D-AD patients showed decreased ReHo in the right precentral gyrus, right superior frontal gyrus, right middle frontal gyrus, and right inferior frontal cortex. Our findings show regional brain activity alterations in D-AD patients. Thus, D-AD pathogenesis may be attributed to abnormal neural activity in multiple brain regions. Show more

Keywords: Alzheimer’s disease, depressive symptoms, regional homogeneity, resting state functional magnetic resonance imaging

DOI: 10.3233/JAD-150460

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 603-611, 2015

Authors: Gramunt, Nina | Buschke, Herman | Sánchez-Benavides, Gonzalo | Lipton, Richard B. | Peña-Casanova, Jordi | Diéguez-Vide, Faustino | Masramon, Xavier | Gispert, Juan D. | Fauria, Karine | Camí, Jordi | Molinuevo, José L.

Article Type: Research Article

Abstract: Background: The Memory Binding Test (MBT) is a novel test based on the learning of two lists of words, developed to detect early memory impairment suggestive of Alzheimer’s disease (AD). Objective: To present and provide reference data of the Spanish MBT in a midlife population of mainly first-degree descendants of AD patients. Methods: 472 cognitively unimpaired subjects, aged 45 to 65 and participants of the ALFA STUDY, were included. Raw scores were transformed to scaled scores on which multivariate regression analysis was applied adjusting by age, gender, and education level. A standard …linear regression was employed to derive the scaled score adjusted. Sociodemographic corrections were applied and an adjustment table was constructed. Results: Performance was heterogeneously influenced by sociodemographic factors. Age negatively influenced free recall. Education tends to have an influence in the results showing lower performance with lower education level. Women tend to outperform men in the learning of the first list and total recall. Only a few variables were unaffected by sociodemographic factors such as those related to semantic proactive interference (SPI) and to the retention of learned material. Our results point out that some vulnerability to SPI is expectable in cognitively healthy subjects. Close to 100% of the learned material was maintained across the delay interval. Conclusion: This study contributes with reference data for the MBT providing the necessary adjustments for sociodemographic characteristics. Our data may prove to be useful for detecting asymptomatic at-risk candidates for secondary prevention studies of AD. Show more

Keywords: Aging, Alzheimer’s disease, cognition, early diagnosis, episodic memory, neuropsychological assessment, preclinical, reference values

DOI: 10.3233/JAD-150237

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 613-625, 2015

Authors: Spalletta, Gianfranco | Long, Jeffrey D. | Robinson, Robert G. | Trequattrini, Alberto | Pizzoli, Sonia | Caltagirone, Carlo | Orfei, Maria D.

Article Type: Research Article

Abstract: Characteristics associated with life expectancy in Alzheimer’s disease (AD) are still far from known. Here we aimed at examining the ability of baseline/longitudinal clinical variables to predict time to death. One-hundred fifty AD outpatients underwent diagnostic, neuropsychiatric, and functional assessment at baseline (when ApoE ɛ 4 was also investigated) and at each subsequent annual visit. A random effects joint modeling approach was used to simultaneously model the baseline and longitudinal trajectory of each factor and predict the time to death, adjusting for demographic covariates. An ancillary analysis of ApoE ɛ 4 status as a predictor was also conducted. Kaplan-Meier survival …curves were constructed to elucidate the relationship between each factor and the estimated probability of death over time. Shorter survival was associated with male gender, higher education, older age, lower cognition, and worse functioning in daily life, but not ApoE ɛ 4 status. Longitudinal trajectories increased predictive power over using just baseline levels highlighting apathy, and secondarily aberrant motor behaviors and sleep disorders, as a highly reliable predictor for mortality. Apathy was the strongest neuropsychiatric predictor of time to death, which supports its role in the pathogenesis of the disorder. An increased knowledge of factors modulating survival in AD is a strategic prerequisite to plan therapeutic interventions. Show more

Keywords: Alzheimer’s disease, apathy, mortality, predictors, prognosis

DOI: 10.3233/JAD-150391

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 627-636, 2015

Authors: Åberg, Daniel | Johansson, Per | Isgaard, Jörgen | Wallin, Anders | Johansson, Jan-Ove | Andreasson, Ulf | Blennow, Kaj | Zetterberg, Henrik | Åberg, N. David | Svensson, Johan

Article Type: Research Article

Abstract: Background: Insulin-like growth factor-II (IGF-II) is important for brain development. Although IGF-II is abundant also in adult life, little is known of the role of IGF-II in Alzheimer’s disease (AD). Objective and methods: This was a cross-sectional study of 60 consecutive patients under primary evaluation of cognitive impairment and 20 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n  = 32), stable MCI (SMCI, n  = 13), or other dementias (n  = 15). IGF-II, IGF-binding protein-1 (IGFBP-1), and IGFBP-2 were analyzed in serum and cerebrospinal fluid (CSF). …Results: Levels of IGF-II, IGFBP-1, and IGFBP-2 were similar in all groups in the total study population. Gender-specific analyses showed that in men (n  = 40), CSF IGF-II level was higher in AD compared to SMCI and controls (p  <  0.01 and p  <  0.05, respectively). Furthermore, CSF IGFBP-2 level was increased in AD men versus SMCI men (p  <  0.01) and tended to be increased versus control men (p  = 0.09). There were no between-group differences in women (n  = 40). In the total study population (n  = 80) as well as in men (n  = 40), CSF levels of IGF-II and IGFBP-2 correlated positively with CSF levels of the AD biomarkers total-tau and phosphorylated tau protein. Conclusion: In men, but not women, in the early stages of AD, CSF IGF-II level was elevated, and CSF IGFBP-2 level tended to be increased, compared to healthy controls. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, IGF-II, IGFBP-1, IGFBP-2, mild cognitive impairment

DOI: 10.3233/JAD-150351

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 637-646, 2015

Authors: Magistri, Marco | Velmeshev, Dmitry | Makhmutova, Madina | Faghihi, Mohammad Ali

Article Type: Research Article

Abstract: The underlying genetic variations of late-onset Alzheimer’s disease (LOAD) cases remain largely unknown. A combination of genetic variations with variable penetrance and lifetime epigenetic factors may converge on transcriptomic alterations that drive LOAD pathological process. Transcriptome profiling using deep sequencing technology offers insight into common altered pathways regardless of underpinning genetic or epigenetic factors and thus represents an ideal tool to investigate molecular mechanisms related to the pathophysiology of LOAD. We performed directional RNA sequencing on high quality RNA samples extracted from hippocampi of LOAD and age-matched controls. We …further validated our data using qRT-PCR on a larger set of postmortem brain tissues, confirming downregulation of the gene encoding substance P (TAC1 ) and upregulation of the gene encoding the plasminogen activator inhibitor-1 (SERPINE1 ). Pathway analysis indicates dysregulation in neural communication, cerebral vasculature, and amyloid-β clearance. Beside protein coding genes, we identified several annotated and non-annotated long noncoding RNAs that are differentially expressed in LOAD brain tissues, three of them are activity-dependent regulated and one is induced by Aβ1 - 42 exposure of human neural cells. Our data provide a comprehensive list of transcriptomics alterations in LOAD hippocampi and warrant holistic approach including both coding and non-coding RNAs in functional studies aimed to understand the pathophysiology of LOAD. Show more

Keywords: Alzheimer’s disease, amyloid homeostasis, cerebral vasculature, long noncoding RNAs, natural antisense transcripts, RNA sequencing

DOI: 10.3233/JAD-150398

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 647-665, 2015

Authors: Kubo, Momoko | Kishi, Taro | Matsunaga, Shinji | Iwata, Nakao

Article Type: Research Article

Abstract: Background: No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of histamine H3 receptor antagonists (H3R-ANTs) in Alzheimer’s disease patients. Objective: We performed a systematic review and meta-analysis of double-blind randomized placebo-controlled trials (RCTs) of H3R-ANTs for Alzheimer’s disease. Methods: Relevant studies were identified through searches of PubMed ® , databases of the Cochrane Library©, and PsycINFO citations up to June 19, 2015. The primary outcome was a change in the Mini-Mental State Examination (MMSE) scores. Secondary outcomes were Neuropsychiatric Inventory (NPI) scores, discontinuation rate, and individual adverse events/side effects. Risk …ratios, numbers-needed-to-treat/harm, and standardized mean differences were calculated based on a random effects model. Results: The computerized search initially yielded 33 studies after excluding duplicates. We excluded 29 of these articles following a review of titles and abstracts and one RCT including healthy subjects after full-text review. We identified three RCTs (two on GSK239512 and one on ABT-288) including 402 patients. Pooled H3R-ANTs were not superior to placebo for improvement in MMSE and NPI scores. Discontinuation rate and individual adverse events/side effects did not differ among the pooled groups. Conclusions: Our results suggest that H3R-ANTs are not effective in treating cognitive dysfunction in Alzheimer’s disease. However, further studies with larger samples are required for definitive conclusions regarding responsive subpopulations. Show more

Keywords: Alzheimer’s disease, histamine H3 receptor antagonist, meta-analysis, systematic review

DOI: 10.3233/JAD-150393

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 667-671, 2015