Journal of Alzheimer's Disease - Volume 58, issue 4

Authors: López-Higes, Ramón | Rodríguez-Rojo, Inmaculada C. | Prados, José M. | Montejo, Pedro | Del-Río, David | Delgado-Losada, María Luisa | Montenegro, Mercedes | López-Sanz, David | Barabash, Ana

Article Type: Research Article

Abstract: Background: Most research points to the ɛ 4 allele of the apolipoprotein E (APOE ) gene as the most recognizable genetic risk factor associated with Alzheimer’s disease pathogenesis. It has been also suggested that the APOE ɛ 4 allele has a negative influence on cognitive functioning, which begins long before cognitive impairment becomes manifest. However, still, little is known about the APOE ɛ 4 interaction with cognitive intervention programs. Objective: The main goal of this study was to explore whether there was a differential APOE genotype modulation effect after cognitive training in different domains, …such as language comprehension, executive functions, and memory. Contrary to other studies, hippocampal volume was controlled for. Methods: Fifty older adults (65+ years; 30 women and 20 men) participated in a multi-domain cognitive training that involved 30 sessions taking place over 12 weeks. Half of the participants were APOE ɛ 4 carriers. The control group was matched in age, gender, normalized hippocampal volume, cognitive reserve, Mini-Mental State Examination score, and Geriatric Depression Scale-Short Version. Results: The study revealed that there were consistent treatment benefits in complex sentence comprehension (noncanonical sentences and sentences with two propositions), a domain that was not directly trained, but only in the A POE ɛ 4 noncarrier group. Conclusion: Genetic profile modulates training outcomes in sentence comprehension. Show more

Keywords: Apolipoprotein E, cognitive training, elderly, neuropsychology

DOI: 10.3233/JAD-161014

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1201-1215, 2017

Authors: Nave, Stephane | Doody, Rachelle S. | Boada, Mercè | Grimmer, Timo | Savola, Juha-Matti | Delmar, Paul | Pauly-Evers, Meike | Nikolcheva, Tania | Czech, Christian | Borroni, Edilio | Ricci, Benedicte | Dukart, Juergen | Mannino, Marie | Carey, Tracie | Moran, Emma | Gilaberte, Inma | Muelhardt, Nicoletta Milani | Gerlach, Irene | Santarelli, Luca | Ostrowitzki, Susanne | Fontoura, Paulo

Article Type: Research Article

Abstract: Background: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer’s disease (AD). Objective: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. Methods: In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13–20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks. Results: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, …was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was – 0.15 (p  = 0.865) and 0.90 (p  = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p  = 0.051) and 1.89 (p  = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: – 2.80 (p  = 0.014; 1 mg) and – 2.64 (p  = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). Conclusions: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline. Show more

Keywords: Alzheimer’s disease, dementia, monoamine oxidase B, Phase II clinical trial

DOI: 10.3233/JAD-161309

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1217-1228, 2017

Authors: Ochoa, John Fredy | Alonso, Joan Francesc | Duque, Jon Edinson | Tobón, Carlos Andrés | Baena, Ana | Lopera, Francisco | Mañanas, Miguel Angel | Hernández, Alher Mauricio

Article Type: Research Article

Abstract: Background: Presenilin-1 (PSEN1) mutations are the most common cause of familial early onset Alzheimer’s disease (AD). The PSEN1 E280A (E280A) mutation has an autosomal dominant inheritance and is involved in the production of amyloid-β. The largest family group of carriers with E280A mutation is found in Antioquia, Colombia. The study of mutation carriers provides a unique opportunity to identify brain changes in stages previous to AD. Electroencephalography (EEG) is a low cost and minimally invasiveness technique that enables the following of brain changes in AD. Objective: To examine how previous reported differences in EEG for Theta and …Alpha-2 rhythms in E280A subjects are related to specific regions in cortex and could be tracked across different ages. Methods: EEG signals were acquired during resting state from non-carriers and carriers, asymptomatic and symptomatic subjects from E280A kindred from Antioquia, Colombia. Independent component analysis (ICA) and inverse solution methods were used to locate brain regions related to differences in Theta and Alpha-2 bands. Results: ICA identified two components, mainly related to the Precuneus, where the differences in Theta and Alpha-2 exist simultaneously at asymptomatic and symptomatic stages. When the ratio between Theta and Alpha-2 is used, significant correlations exist with age and a composite cognitive scale. Conclusion: Theta and Alpha-2 rhythms are altered in E280A subjects. The alterations are possible to track at Precuneus regions using EEG, ICA, and inverse solution methods. Show more

Keywords: Alzheimer’s disease, autosomal-dominant, independent component analysis, inverse solution methods, presenilin-1, quantitative electroencephalography

DOI: 10.3233/JAD-161291

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1229-1244, 2017

Authors: Deters, Kacie D. | Risacher, Shannon L. | Kim, Sungeun | Nho, Kwangsik | West, John D. | Blennow, Kaj | Zetterberg, Henrik | Shaw, Leslie M. | Trojanowski, John Q. | Weiner, Michael W. | Saykin, Andrew J. | for the Alzheimer Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Peripheral (plasma) and central (cerebrospinal fluid, CSF) measures of tau are higher in Alzheimer’s disease (AD) relative to prodromal stages and controls. While elevated CSF tau concentrations have been shown to be associated with lower grey matter density (GMD) in AD-specific regions, this correlation has yet to be examined for plasma in a large study. Objective: Determine the neuroanatomical correlates of plasma tau using voxel-based analysis. Methods: Cross-sectional data for 508 ADNI participants were collected for clinical, plasma total-tau (t-tau), CSF amyloid (Aβ42 ) and tau, and MRI variables. The relationship between plasma tau …and GMD and between CSF t-tau and GMD were assessed on a voxel-by-voxel basis using regression models. Age, sex, APOE ɛ 4 status, diagnosis, and total intracranial volume were used as covariates where appropriate. Participants were defined as amyloid positive (Aβ+) if CSF Aβ42 was <192 pg/mL. Results: Plasma tau was negatively correlated with GMD in the medial temporal lobe (MTL), precuneus, thalamus, and striatum. The associations with thalamus and striatum were independent of diagnosis. A negative correlation also existed between plasma tau and GMD in Aβ+ participants in the MTL, precuneus, and frontal lobe. When compared to CSF t-tau, plasma tau showed a notably different associated brain atrophy pattern, with only small overlapping regions in the fusiform gyrus. Conclusion: Plasma tau may serve as a non-specific marker for neurodegeneration but is still relevant to AD considering low GMD was associated with plasma tau in Aβ+ participants and not Aβ–participants. Show more

Keywords: Alzheimer disease, magnetic resonance imaging, mild cognitive impairment, plasma, tau protein

DOI: 10.3233/JAD-161114

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1245-1254, 2017

Authors: Moon, Byungseung | Kim, Seongheon | Park, Young Ho | Lim, Jae-Sung | Youn, Young Chul | Kim, SangYun | Jang, Jae-Won | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Depressive symptoms are prevalent in patients with mild cognitive impairment (MCI) and are considered to be a risk factor for progression to dementia. Objective: The purpose of this study was to evaluate whether depressive symptoms in MCI promote disease progression in a manner related to amyloid status, and to determine the relationship between depressive symptoms and longitudinal cerebral structural changes. Methods: Baseline data for 336 patients with MCI (75 with depression and 261 without) from the Alzheimer’s Disease Neuroimaging Initiative study were analyzed. All participants underwent comprehensive cognitive testing, volumetric magnetic resonance imaging (MRI), …and [18 F]AV45 positron emission tomography amyloid imaging. Depressive symptoms were measured using the Neuropsychiatric Inventory Questionnaire. A voxel-based morphometric analysis using volumetric brain MRI data was used to compare longitudinal structural changes related to depressive symptoms. Results: The conversion rate to dementia was different between patients with and without depression in amyloid-positive MCI (40.8% versus 19.7%, respectively; p  = 0.006). Patients who were amyloid-positive at baseline also exhibited a greater degree of 2-year cognitive decline. Depression in amyloid-positive MCI was associated with longitudinal cortical atrophy in the left cingulate gyrus. Conclusion: Our study indicates that the presence of depressive symptoms in patients with amyloid-positive MCI is associated with higher progression to dementia and longitudinal cortical atrophy. Show more

Keywords: Alzheimer’s disease, depression, mild cognitive impairment

DOI: 10.3233/JAD-170225

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1255-1264, 2017

Authors: Cermakova, Pavla | Nelson, Maja | Secnik, Juraj | Garcia-Ptacek, Sara | Johnell, Kristina | Fastbom, Johan | Kilander, Lena | Winblad, Bengt | Eriksdotter, Maria | Religa, Dorota

Article Type: Research Article

Abstract: Background: Many people with Alzheimer’s disease (AD) live alone in their own homes. There is a lack of knowledge about whether these individuals receive the same quality of diagnostics and treatment for AD as patients who are cohabiting. Objectives: To investigate the diagnostic work-up and treatment of community-dwelling AD patients who live alone. Methods: We performed a cross-sectional cohort study based on data from the Swedish Dementia Registry (SveDem). We studied patients diagnosed with AD between 2007 and 2015 (n  = 26,163). Information about drugs and comorbidities was acquired from the Swedish Prescribed Drug Register and …the Swedish Patient Register. Results: 11,878 (46%) patients lived alone, primarily older women. After adjusting for confounders, living alone was inversely associated with receiving computed tomography (OR 0.90; 95% CI 0.82–0.99), magnetic resonance imaging (OR 0.91; 95% CI 0.83–0.99), and lumbar puncture (OR 0.86; 95% CI 0.80–0.92). Living alone was also negatively associated with the use of cholinesterase inhibitors (OR 0.81; 95% CI 0.76; 0.87), memantine (OR 0.77; 95% CI 0.72; 0.83), and cardiovascular medication (OR 0.92; 0.86; 0.99). On the other hand, living alone was positively associated with the use of antidepressants (OR 1.15; 95% CI 1.08; 1.22), antipsychotics (OR 1.41; 95% CI 1.25; 1.58), and hypnotics and sedatives (OR 1.09; 95% CI 1.02; 1.17). Conclusions: Solitary living AD patients do not receive the same extent of care as those who are cohabiting. Show more

Keywords: Alzheimer’s disease, dementia, diagnostics, solitary living, treatment

DOI: 10.3233/JAD-170102

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1265-1272, 2017

Authors: Pink, Anna | Przybelski, Scott A. | Krell-Roesch, Janina | Stokin, Gorazd B. | Roberts, Rosebud O. | Mielke, Michelle M. | Knopman, David S. | Jack Jr., Clifford R. | Petersen, Ronald C. | Geda, Yonas E.

Article Type: Research Article

Abstract: Altered cortical thickness has been observed in aging and various neurodegenerative disorders. Furthermore, reduced hippocampal volume has been reported in late-life depression. Even mild depressive symptoms are common in the elderly. However, little is known about the structural MRI measures of depressive symptoms in normal cognitive aging. Thus we sought to examine the association between depressive symptoms with cortical thickness and hippocampal volume as measured by brain MRI among community-dwelling participants. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging, involving cognitively normal participants (N  = 1,507) aged≥70 years. We observed that depressive symptoms were …associated with lower global cortical thickness and lower thickness in specific prefrontal and temporal cortical regions, labeled by FreeSurfer software, version 5.3. As expected, the strength of correlation was very small, given that participants were community-dwelling with only mild depressive symptoms. We did not observe associations between hippocampal volume and depressive symptoms. These findings may provide insight into the structural correlates of mild depressive symptoms in elderly participants. Show more

Keywords: Aging, cortical thickness, depression, depressive symptoms, magnetic resonance imaging

DOI: 10.3233/JAD-170041

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1273-1281, 2017

Authors: Gu, Lihua | Zhang, Zhijun

Article Type: Research Article

Abstract: Background: Early diagnosis and effective management are pivotal steps in preventing the transition from mild cognitive impairment (MCI) to Alzheimer’s disease. Previous investigations indicated that some event-related potential (ERP) components in MCI are sensitive to cognitive decline. However, several comparative analyses of these components in MCI and healthy controls (HC) yielded inconsistent results. Objective: The aim was to perform a systematic review and meta-analysis of ERP studies on MCI patients. Methods: We systematically searched on PubMed and Web of Science for MCI-related ERP studies published from April 1986 to August 2016. Standard mean difference estimates …of all components were compared between MCI and HC. Results: Our study showed increased P50 amplitude at the Cz site; reduced N2pc amplitude and delayed P200 latency at the Cz site; N200 latency at the Cz and Pz sites, and P300 latency at the Cz and Pz sites in MCI patients compared to HC. Conclusions: In summary, our study indicated that some ERP components, such as P50 and N2pc amplitude, P200, N200, and P300 latency might be potential electrophysiological biomarkers for MCI diagnosis. Show more

Keywords: Event-related potential, meta-analysis, mild cognitive impairment

DOI: 10.3233/JAD-161286

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1283-1292, 2017

Authors: Lim, Yen Ying | Williamson, Robert | Laws, Simon M. | Villemagne, Victor L. | Bourgeat, Pierrick | Fowler, Christopher | Rainey-Smith, Stephanie | Salvado, Olivier | Martins, Ralph N. | Rowe, Christopher C. | Masters, Colin L. | Maruff, Paul | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: The association between the apolipoprotein E (APOE ) ɛ 4 allele and high risk of developing Alzheimer’s disease (AD) dementia before the age of 80 has been recognized for over 30 years. However, the timing and mode of action of APOE is not understood, nor has there been a detailed analysis of the effect of APOE genotype on memory, hippocampal volume, and amyloid-β (Aβ) levels in cognitively normal adults. Objective: Examine the effect of APOE allelic genotype on the relationship between Aβ levels, hippocampal volume, and memory in cognitively normal adults. Methods: …This is a cross-sectional study of 989 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, all of whom underwent APOE genotyping and memory assessment. A subset of this group underwent PET neuroimaging for Aβ (n  = 585) and MRI for hippocampal volume (n  = 303). Results: APOE ɛ 4 homozygotes (ɛ 4/ɛ 4) showed significantly worse episodic memory and higher Aβ levels than ɛ 4 heterozygotes. The relationship between increasing Aβ levels and worse episodic memory was significant for ɛ 3 homozygotes (ɛ 3/ɛ 3), ɛ 4 heterozygotes, and strongest for ɛ 4 homozygotes. There were no differences in hippocampal volume between APOE groups; the relationship between smaller hippocampal volume and worse episodic memory was significant only for ɛ 4 homozygotes. Conclusion: APOE acts in a co-dominant fashion on Aβ levels, episodic memory, and hippocampal volume in cognitively normal older adults. APOE ɛ 4 is central to the events that lead to AD in cognitively normal older adults, likely through a quantitative role in the disruption of Aβ clearance. Show more

Keywords: Alzheimer’s disease, amyloid, apolipoprotein E, hippocampal volume, memory, mild cognitive impairment

DOI: 10.3233/JAD-170072

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1293-1302, 2017

Authors: Busse, Mandy | Michler, Enrico | von Hoff, Franz | Dobrowolny, Henrik | Hartig, Roland | Frodl, Thomas | Busse, Stefan

Article Type: Research Article

Abstract: Alterations in the immune response that result in inflammation might play a role in the pathology of dementias. In order to analyze changes of the peripheral immune system associated with different types of dementias, we determined several innate and adaptive cell populations in whole blood using flow cytometry. We included patients with Alzheimer’s disease (AD; n  = 60), vascular dementia (VaD; n  = 20), and frontotemporal dementia (FTD; n  = 12) at the time point of diagnosis and 24 age-matched neuropsychiatric healthy persons. Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers …were decreased in all investigated forms of dementia. Changes in the contribution of naïve/memory T cells were only present in AD. Correlation and regression analyses revealed associations between altered immune cell populations and Q Albumin as marker for the integrity of the blood-cerebrospinal fluid-barrier, Mini-Mental State Examination values, and age. The peripheral immune system is altered in AD, VaD, and FTD. However, each disorder presents unique changes in the investigated cell types indicating different mechanisms underlying the pathology. Show more

Keywords: Alzheimer’s disease, B cells, frontotemporal dementia, monocytes, NK cells, T cells, vascular dementia

DOI: 10.3233/JAD-161304

Citation: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1303-1313, 2017