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

Authors: Di Stefano, Francesca | Epelbaum, Stephane | Coley, Nicola | Cantet, Christelle | Ousset, Pierre-Jean | Hampel, Harald | Bakardjian, Hovagim | Lista, Simone | Vellas, Bruno | Dubois, Bruno | Andrieu, Sandrine | for the GuidAge study group

Article Type: Research Article

Abstract: In therapeutic trials, it is crucial to identify Alzheimer’s disease (AD) at its prodromal stage. We assessed the accuracy of the free and cued selective reminding test (FCSRT) compared to other cognitive tests to predict AD dementia in subjects with subjective cognitive decline or mild cognitive impairment. Subjects from the placebo group of the GuidAge trial over 70 years old and without clinical signs of dementia at baseline who completed the 5-year follow-up free of dementia (n  = 840) or developed AD dementia (n  = 73) were included in our study. Among all the tests, the sum of the 3 free recall …of the FCSRT (FCSRT-FR) and the sum of free and cued recall (FCSRT-TR) yielded the best results to predict AD dementia occurrence (all p values <0.05 for comparison of FCSRT-FR ROC and MMSE, CDRsb, and CVF ROCs). FCSRT-FR had an area under the ROC curve of 0.799 (95% CI 0.738–0.85) and the optimal cut-off was 20 (se 68.06% , sp 81.43% , PPV 23.90% , NPV 96,75%). Concerning FCSRT-TR, the AUC was 0.776 and the optimal cut-off was 42 (se 62.5% , sp 82.26% , PPV 23.20% and NPV 96.24%). This study sets the framework for implementing the FCSRT in clinical and therapeutic trials for efficient subject selection. Show more

Keywords: Alzheimer’s disease, free and cued selective reminding test, IWG criteria, prodromal, subjective cognitive decline

DOI: 10.3233/JAD-150013

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 793-804, 2015

Authors: Eriksdotter, Maria | Vedin, Inger | Falahati, Farshad | Freund-Levi, Yvonne | Hjorth, Erik | Faxen-Irving, Gerd | Wahlund, Lars-Olof | Schultzberg, Marianne | Basun, Hans | Cederholm, Tommy | Palmblad, Jan

Article Type: Research Article

Abstract: Background: ω3 fatty acids (ω3 FAs) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer’s disease (AD). However, the relationship between changes of plasma ω3 FA levels and cognitive performance, as well as effects of gender, are poorly known. Objective: To study the effect of 6-month administration of DHA-rich ω3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender. This investigation is part of the OmegAD Study. Methods: 174 AD patients (74 ± 9 years) were …randomized to a daily intake of 2.3 g ω3 FA or placebo for 6 months; subsequently all received the ω3 FA preparation for the next 6 months. Baseline as well as changes in plasma levels of the main ω3 FAs in 165 patients, while receiving ω3 FA supplementation for 6 months, were analyzed for association to cognitive performance (assessed by ADAS-cog and MMSE scores) as well as to gender. Results: Preservation of cognitive functioning, assessed by ADAS-cog or its sub-items (but not MMSE) scores, was significantly associated to increasing plasma ω3 FA levels over time. Thus, the higher ω3 FA plasma levels rose, the lower was the rate of cognitive deterioration. This effect was not related to gender; since although females displayed higher ω3 FA plasma levels than did males after 6 months of supplementation, this difference disappeared when adjusted for body weight. Conclusions: Since our study suggests dose-response relationships between plasma levels of ω3 FA and preservation of cognition, future ω3 FA trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of ω3 FA. Show more

Keywords: Alzheimer’s disease, cognition, DHA, EPA, gender, ω3 fatty acids, ClinicalTrials.gov identifier: NCT00211159

DOI: 10.3233/JAD-150102

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 805-812, 2015

Authors: Hilal, Saima | Amin, Shaik Muhammad | Venketasubramanian, Narayanaswamy | Niessen, Wiro J. | Vrooman, Henri | Wong, Tien Yin | Chen, Christopher | Ikram, Mohammad Kamran

Article Type: Research Article

Abstract: Background: Cortical atrophy is a key neuroimaging feature of dementia. However, the role of subcortical gray matter reduction in cognitive impairment has not been explored extensively. Objectives: We examined the risk factors of subcortical structures on neuroimaging and their association with cognitive impairment and dementia. Methods: Data from two studies were used: a subsample from the Epidemiology of Dementia in Singapore (EDIS) study of non-demented community-dwelling subjects (n  = 550) and a case-control study. Subjects underwent similar neuropsychological tests and brain MRI. Subcortical volumes of accumbens, amygdala, caudate, pallidum, putamen, thalamus, hippocampus, and brainstem were measured. …Cognitive impairment no dementia (CIND), dementia and its subtypes, vascular cognitive impairment (VCI), were defined using accepted criteria. Cognitive function was also expressed as both composite and domain-specific Z-scores. Results: In the EDIS study, age, female gender, Malay ethnicity, diabetes, lacunar-infarcts, and white matter lesions were the most important risk factors for subcortical atrophy. Moreover, smaller volumes of accumbens, amygdala, caudate, thalamus, and brainstem were significantly associated with lower cognitive composite Z-scores. With respect to clinical outcomes in the case-control study, structures such as the accumbens, caudate, putamen, and hippocampus were associated with both CIND and dementia. Smaller caudate and pallidum volumes were related to VCI whereas amygdalar atrophy was only associated with non-VCI. Furthermore, subcortical atrophy was related to both VCI and non-VCI. Conclusion: Subcortical gray matter atrophy is not only observed in dementia, but also in the preclinical stages of cognitive impairment. Furthermore, besides VCI, subcortical structures were also related to non-VCI. Show more

Keywords: Cognitive impairment, magnetic resonance imaging, risk factors, subcortical atrophy

DOI: 10.3233/JAD-150473

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 813-823, 2015

Authors: Diehl-Wiesenecker, Eva | von Arnim, Christine A.F. | Dupuis, Luc | Müller, Hans-Peter | Ludolph, Albert C. | Kassubek, Jan

Article Type: Research Article

Abstract: Background: Total and central adiposity have been associated with increased risk of Alzheimer’s disease (AD). Visceral and subcutaneous adipose tissues have different metabolic characteristics and could therefore be differentially associated with AD. Objective: To compare regional fat distribution determined by magnetic resonance imaging (MRI) in AD patients and healthy controls and investigate associations with stage of the disease and chemical markers. The investigation was performed in a prospective case-control study. Methods: We examined thirty patients with mild to moderate AD by whole-body MRI (1.5 T) and clinical questionnaires in comparison to thirty …cognitively healthy age- and gender-matched study participants. Volumes of total, subcutaneous, and visceral body fat tissue were determined by an unbiased automatic analysis algorithm. Levels of leptin, ghrelin, and adiponectin were determined in serum, amyloid-β (Aβ)1-42 and tau protein levels in cerebrospinal fluid (CSF). Results: Male AD patients displayed significantly more total fat tissue than male controls. This difference was not observed in women. We observed a trend toward higher volume of visceral fat tissue in all patients (p  = 0.13). Severity of disease was not associated with fat distribution in our study. Increased leptin levels correlated with lower CSF Aβ1-42 in female, but not in male, AD patients. Conclusions: Fat volume is increased in male, but not in female AD patients. Negative correlation of leptin levels and CSF Aβ1-42 in females might be one co-factor for the increased AD risk of females. Further studies are required to confirm this gender difference in fat volume during AD and evaluate its pathophysiological importance. Show more

Keywords: Leptin, magnetic resonance imaging, subcutaneous fat, visceral fat

DOI: 10.3233/JAD-150426

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 825-832, 2015

Authors: Price, Catherine C. | Tanner, Jared J. | Schmalfuss, Ilona M. | Brumback, Babette | Heilman, Kenneth M. | Libon, David J.

Article Type: Research Article

Abstract: Background: There is remarkable heterogeneity in clinical Alzheimer’s disease (AD) or vascular dementia (VaD). Objectives: 1) To statistically examine neuropsychological data to determine dementia subgroups for individuals clinically diagnosed with AD or VaD and then 2) examine group differences in specific gray/white matter regions of interest. Methods: A k-means cluster analysis requested a 3-group solution from neuropsychological data acquired from individuals diagnosed clinically with AD/VaD. MRI measures of hippocampal, caudate, ventricular, subcortical lacunar infarction, whole brain volume, and leukoaraiosis (LA) were analyzed. Three regions of LA volumes were quantified and these included …the periventricular (5 mm around the ventricles), infracortical (5 mm beneath the gray matter), and deep (between periventricular and infracortical) regions. Results: Cluster analysis sorted AD/VaD patients into single domain amnestic (n  = 41), single-domain dysexecutive (n  = 26), and multi-domain (n  = 26) phenotypes. Multi-domain patients exhibited worst performance on language tests; however, multi-domain patients were equally impaired on memory tests when compared to amnestic patients. Statistically-determined groups dissociated using neuroradiological parameters: amnestic and multi-domain groups presented with smaller hippocampal volume while the dysexecutive group presented with greater deep, periventricular, and whole brain LA. Neither caudate nor lacunae volume differed by group. Caudate nucleus volume negatively correlated with total LA in the dysexecutive and multi-domain groups. Conclusions: There are at least three distinct subtypes embedded within patients diagnosed clinically with AD/VaD spectrum dementia. We encourage future research to assess a) the neuroradiological substrates underlying statistically-determined AD/VaD spectrum dementia and b) how statistical modeling can be integrated into existing diagnostic criteria. Show more

Keywords: Caudate nucleus, executive function, hippocampus, lacune, learning, leukoaraiosis, memory, Philadelphia (repeatable) Verbal Learning Test, ventricles, white matter abnormalities

DOI: 10.3233/JAD-150407

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 833-847, 2015

Authors: Kuntz, Mélanie | Candela, Pietra | Saint-Pol, Julien | Lamartinière, Yordenca | Boucau, Marie-Christine | Sevin, Emmanuel | Fenart, Laurence | Gosselet, Fabien

Article Type: Research Article

Abstract: One of the prime features of Alzheimer’s disease (AD) is the excessive accumulation of amyloid-β (Aβ) peptides in the brain. Several recent studies suggest that this phenomenon results from the dysregulation of cholesterol homeostasis in the brain and impaired bidirectional Aβ exchange between blood and brain. These mechanisms appear to be closely related and are controlled by the blood-brain barrier (BBB) at the brain microvessel level. In animal models of AD, the anticancer drug bexarotene (a retinoid X receptor agonist) has been found to restore cognitive functions and decrease the brain amyloid burden by regulating cholesterol homeostasis. However, the drug’s …therapeutic effect is subject to debate and the exact mechanism of action has not been characterized. Therefore, the objective of this present study was to determine bexarotene’s effects on the BBB. Using an in vitro model of the human BBB, we investigated the drug’s effects on cholesterol exchange between abluminal and luminal compartments and the apical-to-basolateral transport of Aβ peptides across the BBB. Our results demonstrated that bexarotene induces the expression of ABCA1 but not ApoE. This upregulation correlates with an increase in ApoE2-, ApoE4-, ApoA-I-, and HDL-mediated cholesterol efflux. Regarding the transport of Aβ peptides, bexarotene increases the expression of ABCB1, which in turn decreases Aβ apical-to-basolateral transport. Our results showed that bexarotene not only promotes the cholesterol exchange between the brain and the blood but also decreases the influx of Aβ peptides across BBB, suggesting that bexarotene is a promising drug candidate for the treatment of AD. Show more

Keywords: ABCA1, ABCB1, Aβ peptide, bexarotene, blood-brain barrier, cholesterol, RAGE, RXR

DOI: 10.3233/JAD-150469

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 849-862, 2015

Authors: You, S. Christine | Walsh, Christine M. | Chiodo, Louis A. | Ketelle, Robin | Miller, Bruce L. | Kramer, Joel H.

Article Type: Research Article

Abstract: Background: Cognitive deficits are presumed to be the primary driver of functional impairment in Alzheimer’s disease (AD); however, functional impairment is likely multifactorially determined. Objective: Our objective was to determine the relative contribution of neuropsychiatric symptoms in predicting ratings of functional status. Methods: A total of 223 patients received routine neurological and neuropsychological evaluations and met criteria of probable AD dementia based on the McKhann criteria. Demographic, cognitive, and neuropsychiatric variables were entered in a hierarchical linear regression analysis to predict functional status as measured by the Functional Activities Questionnaire (FAQ). …Results: The total model explained 29.7% of the variance (p  <  0.001) in FAQ. Importantly, neuropsychiatric variables explained 12.7% of the unique variance, with apathy and sleep as significant contributors. Conclusion: Two neuropsychiatric variables, apathy and changes in sleep/nighttime behaviors, predicted ratings of functional status in AD patients independent of age, global cognition, memory and executive function measures, and depressive symptoms. These results highlight the importance of neuropsychiatric symptoms in understanding and potentially treating the functional limitations so prevalent in AD. Show more

Keywords: Alzheimer’s disease, apathy, neuropsychology, sleep disorders

DOI: 10.3233/JAD-150018

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 863-869, 2015

Article Type: Other

DOI: 10.3233/JAD-150647

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 871-874, 2015

Authors: Huang, Rong | Wang, Pin | Han, Jing | Xia, Wenqing | Cai, Rongrong | Sun, Haixia | Sun, Jie | Wang, Shaohua

Article Type: Correction

DOI: 10.3233/JAD-159003

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 875-875, 2015

Authors: Arab, L. | Sabbagh, M.N.

Article Type: Correction

DOI: 10.3233/JAD-159004

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 877-877, 2015