Journal of Alzheimer's Disease - Volume 49, issue 4

Authors: Dlugaj, Martha | Winkler, Angela | Weimar, Christian | Dürig, Jan | Broecker-Preuss, Martina | Dragano, Nico | Moebus, Susanne | Jöckel, Karl-Heinz | Erbel, Raimund | Eisele, Lewin

Article Type: Research Article

Abstract: There is increasing evidence that anemia is associated with cognitive impairment. Therefore, the aim of the study was to examine the cross-sectional association of anemia as well as the persistence of anemia over the last five years with mild cognitive impairment (MCI) and MCI subtypes (amnestic/non-amnestic MCI (aMCI/naMCI)). Out of 4,157 participants (50% men, 50–80 years) of the second examination (t1 ) of a cohort study (baseline (t0 ) 2000–2003), we included 4,033 participants with available hemoglobin information and complete cognitive assessment. Anemia was defined as hemoglobin <13 g/dl in men (n  = 84) and <12 g/dl in women (n  = 79). Group comparisons …were used to compare the cognitive subtests. To determine the association of MCI with anemia at t1 , with anemia five years prior to the cognitive assessment (t0 ) and anemia at both time points, we used logistic regression models and included 579 participants with MCI and 1,438 cognitively normal participants out of the total cohort. Anemic participants showed lower performances in verbal memory and executive functions. The fully adjusted odds ratios (OR) for MCI, aMCI, and naMCI in anemic versus non-anemic participants were 1.92 (95% -CI, 1.09–3.39), 1.96 (1.00–3.87), and 1.88 (0.91–3.87). Anemia at both times points showed a non-significant association with naMCI (OR 3.74, 0.94–14.81, fully adjusted). Our results suggest that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. The association of anemia and MCI has important clinical relevance, because many causes of anemia can be treated effectively. Show more

Keywords: Aging, anemia, epidemiology, MCI, mild cognitive impairment

DOI: 10.3233/JAD-150434

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1031-1042, 2016

Authors: Stogmann, Elisabeth | Moser, Doris | Klug, Stefanie | Gleiss, Andreas | Auff, Eduard | Dal-Bianco, Peter | Pusswald, Gisela | Lehrner, Johann

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) may be an early indicator for an increased risk of dementia. The exact definition of SCD remains unclear and has recently become a major research interest. Objectives: To determine impairments in activities of daily living (ADL) and depressive symptoms in elderly individuals with SCD, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Methods: We included 752 consecutive patients suffering from SCD, non-amnestic (naMCI) or amnestic MCI (aMCI), AD, and 343 healthy controls into this prospective cohort study. A neuropsychological test battery, B-ADL and BDI-II was performed. Results: SCD patients …showed a decreased performance in ADL compared to controls. Performance in ADL declined concurrently with cognitive abilities along the controls−SCD−naMCI−aMCI−AD continuum. Individuals with cognitive complains, no matter if SCD, MCI, or AD patients, reported more often depressive symptoms compared to healthy controls without complaints. Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. Adjusting for depressive symptoms, there was no significant group difference between the control versus the SCD group (OR 1.1, CI 0.6–1.7). Conclusions: SCD is a heterogeneous clinical condition. Specific features such as slightly impaired ADL and depressive symptoms are associated with SCD. Clinical markers may serve as an indicator for preclinical AD and in combination with biomarkers guide to an early diagnosis of a progressive neurodegenerative disease. Show more

Keywords: Activities of daily living, Alzheimer’s Disease, depressive symptoms, mild cognitive impairment subtypes, subjective cognitive decline

DOI: 10.3233/JAD-150785

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1043-1050, 2016

Authors: Liu, Jieqiong | Zhang, Xinqing | Yu, Chunshui | Duan, Yunyun | Zhuo, Junjie | Cui, Yue | Liu, Bing | Li, Kuncheng | Jiang, Tianzi | Liu, Yong

Article Type: Research Article

Abstract: Background: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases. Objective: To investigate if disease severity associated altered PHG connectivity in Alzheimer’s disease (AD) exists. Methods: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson’s correlation coefficients between the bilateral PHG and whole brain. …Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability. Results: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini-Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe. Conclusions: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD. Show more

Keywords: Alzheimer’s disease, functional connectivity, mild cognitive impairment, parahippocampus

DOI: 10.3233/JAD-150727

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1051-1064, 2016

Authors: Bertoux, Maxime | de Souza, Leonardo Cruz | O’Callaghan, Claire | Greve, Andrea | Sarazin, Marie | Dubois, Bruno | Hornberger, Michael

Article Type: Research Article

Abstract: Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer’s disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the …short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ∼50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD. Show more

Keywords: Alzheimer’s disease, amnesia, differential diagnosis, frontotemporal dementia, episodic memory, neuropsychology, social-cognition

DOI: 10.3233/JAD-150686

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1065-1074, 2016

Authors: Le Bouc, Raphael | Marelli, Cecilia | Beaufils, Emilie | Berr, Claudine | Hommet, Caroline | Touchon, Jacques | Pasquier, Florence | Deramecourt, Vincent

Article Type: Research Article

Abstract: Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, …and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families’ negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians’ rate of making requests and the public’s awareness about the importance of brain donation. Show more

Keywords: Alzheimer’s disease, brain bank, brain donation, neurodegenerative diseases, postmortem examination

DOI: 10.3233/JAD-150825

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1075-1083, 2016

Authors: Tosto, Giuseppe | Monsell, Sarah E. | Hawes, Stephen E. | Bruno, Giuseppe | Mayeux, Richard

Article Type: Research Article

Abstract: Background: Extrapyramidal signs (EPS) are frequent in Alzheimer’s disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson’s disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions. Objective: To identify clusters of EPS progression over time and their clinical and neuropathological correlates. Methods: 3,502 AD patients with longitudinal assessment from the National Alzheimer’s Coordinating Center database were included; 394 provided neuropathological data. k-means algorithm was employed to identify clusters of EPS progression and those were compared in terms of cognitive profile, neuropsychiatric features and neuropathological findings. …Results: Three clusters of EPS progression were identified: no/low (n  = 1,583), medium (n  = 1,259), and high (n  = 660) EPS burden. Compared to those with no/low and medium EPS, those with high EPS had greater cognitive and neuropsychiatric impairment, specifically hallucinations. Despite similar AD-pathology across the three clusters, the high EPS cluster had a significantly number of subjects diagnosed with dementia with Lewy bodies. Conclusions: Cluster analysis of EPS progression over time identified different subgroups of AD patients with distinct clinical and neuropathological features. Show more

Keywords: Alzheimer’s disease, extrapyramidal signs, Lewy bodies, longitudinal studies, K-means clustering

DOI: 10.3233/JAD-150244

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1085-1093, 2016

Authors: McGuinness, Bernadette | Fuchs, Marc | Barrett, Suzanne L. | Passmore, A. Peter | Johnston, Janet A.

Article Type: Research Article

Abstract: A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer’s disease (AD) would be invaluable. Previous pilot studies by our group identified elevated platelet membrane β-secretase activity in patients with AD and MCI, as compared to controls, and this activity was influenced by membrane cholesterol levels. The present study investigated baseline platelet membrane β-secretase activity and cholesterol levels in 97 MCI participants and 85 controls and explored whether these parameters differed in individuals with stable MCI, as compared to those who subsequently developed AD. To evaluate …signal specificity, β-secretase activity assays were conducted in the presence and absence of beta-site amyloid-β protein precursor-cleaving enzyme (BACE) inhibitors. Baseline platelet membrane β-secretase activity did not differ significantly in MCI participants, as compared to controls, and platelet membrane cholesterol levels were significantly lower in the MCI group. The longitudinal study indicated that the activities inhibited by two different BACE inhibitors did not predict conversion to AD; however, the activity that was not affected by BACE inhibitors was significantly (40%) higher in individuals with stable MCI, as compared with those who subsequently developed AD. These findings indicated that further research into the source of this activity could contribute to a measure facilitating prediction of the risk of conversion from MCI to AD. Show more

Keywords: Amyloid-β protein precursor, beta-site amyloid-β protein precursor-cleaving enzyme, cognition, dementia, Neuropsychology, protease inhibitor

DOI: 10.3233/JAD-150795

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1095-1103, 2016

Authors: Sattlecker, Martina | Khondoker, Mizanur | Proitsi, Petroula | Williams, Stephen | Soininen, Hilkka | Kłoszewska, Iwona | Mecocci, Patrizia | Tsolaki, Magda | Vellas, Bruno | Lovestone, Simon | Dobson, Richard JB

Article Type: Research Article

Abstract: Biomarkers of Alzheimer’s disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across …disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects. Show more

Keywords: Alzheimer’s disease, cognitive decline, complement cascade, cytokine-cytokine receptor interaction, plasma proteins

DOI: 10.3233/JAD-140669

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1105-1114, 2016

Authors: Zwan, Marissa D. | Villemagne, Victor L. | Doré, Vincent | Buckley, Rachel | Bourgeat, Pierrick | Veljanoski, Robyn | Salvado, Olivier | Williams, Rob | Margison, Laura | Rembach, Alan | Macaulay, S. Lance | Martins, Ralph | Ames, David | van der Flier, Wiesje M. | Ellis, Kathryn A. | Scheltens, Philip | Masters, Colin L. | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: APOE ɛ 4 genotype and aging have been identified as risk factors for Alzheimer’s disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning. Objective: To assess whether APOE ɛ 4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly. Methods: 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression …analyses were performed to determine the association of APOE ɛ 4 genotype, age, SMC, and episodic memory with Aβ pathology. Results: Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68–6.14), when SMC were present (OR = 1.90; 95% CI = 1.03–3.48), and for APOE ɛ 4 carriers (OR = 7.49; 95% CI = 3.96–14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOE ɛ 4 carriers (OR = 4.58, 95% CI = 1.83–11.49) and younger participants (OR = 3.73, 95% CI = 1.39–10.01). Conclusion: Aging, APOE ɛ 4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOE ɛ 4 carriers. These findings suggest that selection based on the presence of SMC, APOE ɛ 4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials. Show more

Keywords: Aging, amyloid-β, apolipoprotein E, [11C]-PiB, episodic memory, [18F]flutemetamol, positron emission tomography

DOI: 10.3233/JAD-150446

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1115-1122, 2016

Authors: Novak, Gerald | Fox, Nick | Clegg, Shona | Nielsen, Casper | Einstein, Steven | Lu, Yuan | Tudor, Iulia Cristina | Gregg, Keith | Di, Jianing | Collins, Peter | Wyman, Bradley T. | Yuen, Eric | Grundman, Michael | Brashear, H. Robert | Liu, Enchi

Article Type: Research Article

Abstract: Background: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE* ɛ 4 carriers and noncarriers, respectively, with Alzheimer’s disease. Objectives: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change. Methods: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures. Results: For BBSI and …HBSI, there were no significant treatment-related differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers. Conclusions: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences. Show more

Keywords: Alzheimer’s disease, bapineuzumab, brain boundary shift integral, brain volume, hippocampal boundary shift integral, magnetic resonance imaging, randomized controlled trial, ventricular boundary shift integral, ventricular volume

DOI: 10.3233/JAD-150448

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1123-1134, 2016