Journal of Alzheimer's Disease - Volume 44, issue 2

Authors: Nowrangi, Milap A. | Okonkwo, Ozioma | Lyketsos, Constantine | Oishi, Kenichi | Mori, Susumu | Albert, Marilyn | Mielke, Michelle M.

Article Type: Research Article

Abstract: Impairment in executive function (EF) is commonly found in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Atlas-based diffusion tensor imaging (DTI) methods may be useful in relating regional integrity to EF measures in MCI and AD. Sixty-six participants (25 normal controls, 22 MCI, and 19 AD) received DTI scans and clinical evaluation. DTI scans were applied to a pre-segmented atlas and fractional anisotropy (FA) and mean diffusivity (MD) were calculated. ANOVA was used to assess group differences in frontal, parietal, and cerebellar regions. For regions differing between groups (p < 0.01), linear regression examined the relationship between EF scores …and regional FA and MD. Anisotropy and diffusivity in frontal and parietal lobe white matter structures were associated with EF scores in MCI and only frontal lobe structures in AD. EF was more strongly associated with FA than MD. The relationship between EF and anisotropy and diffusivity was strongest in MCI. These results suggest that regional white matter integrity is compromised in MCI and AD and that FA may be a better correlate of EF than MD. Show more

Keywords: Alzheimer's disease, diffusion tensor imaging executive function, mild cognitive impairment

DOI: 10.3233/JAD-141937

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 585-598, 2015

Authors: Tang, Xiaoying | Holland, Dominic | Dale, Anders M. | Younes, Laurent | Miller, Michael I. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: In this paper, we propose a novel predictor for the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). This predictor is based on the shape diffeomorphometry patterns of subcortical and ventricular structures (left and right amygdala, hippocampus, thalamus, caudate, putamen, globus pallidus, and lateral ventricle) of 607 baseline scans from the Alzheimer's Disease Neuroimaging Initiative database, including a total of 210 healthy control subjects, 222 MCI subjects, and 175 AD subjects. The optimal predictor is obtained via a feature selection procedure applied to all of the 14 sets of shape features via linear discriminant analysis, resulting in a …combination of the shape diffeomorphometry patterns of the left hippocampus, the left lateral ventricle, the right thalamus, the right caudate, and the bilateral putamen. Via 10-fold cross-validation, we substantiate our method by successfully differentiating 77.04% (104/135) of the MCI subjects who converted to AD within 36 months and 71.26% (62/87) of the non-converters. To be specific, for the MCI-converters, we are capable of correctly predicting 82.35% (14/17) of subjects converting in 6 months, 77.5% (31/40) of subjects converting in 12 months, 74.07% (20/27) of subjects converting in 18 months, 78.13% (25/32) of subjects converting in 24 months, and 73.68% (14/19) of subject converting in 36 months. Statistically significant correlation maps were observed between the shape diffeomorphometry features of each of the 14 structures, especially the bilateral amygdala, hippocampus, lateral ventricle, and two neuropsychological test scores—the Alzheimer's Disease Assessment Scale-Cognitive Behavior Section and the Mini-Mental State Examination. Show more

Keywords: Alzheimer's disease, lateral ventricles, linear discriminant analysis, mild cognitive impairment, prediction, principal component analysis, shape diffeomorphometry, subcortical structures

DOI: 10.3233/JAD-141605

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 599-611, 2015

Authors: Barucker, Christian | Sommer, Anette | Beckmann, Georg | Eravci, Murat | Harmeier, Anja | Schipke, Carola G. | Brockschnieder, Damian | Dyrks, Thomas | Althoff, Veit | Fraser, Paul E. | Hazrati, Lili-Naz | George-Hyslop, Peter St | Breitner, John C.S. | Peters, Oliver | Multhaup, Gerhard

Article Type: Research Article

Abstract: The pathogenesis of Alzheimer's disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA …microarray study showed that Aβ42 , at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers. Show more

Keywords: Alzheimer's disease, amyloid-β, CSF proteomics, gene regulation, ID1-3, IGFBP, immunohistochemistry, LMO4, transcription factors

DOI: 10.3233/JAD-141902

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 613-624, 2015

Authors: Egli, Simone C. | Hirni, Daniela I. | Taylor, Kirsten I. | Berres, Manfred | Regeniter, Axel | Gass, Achim | Monsch, Andreas U. | Sollberger, Marc

Article Type: Research Article

Abstract: Background: Several cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers predict conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, predictors might be more or less powerful depending on the characteristics of the MCI sample. Objective: To investigate which cognitive markers and biomarkers predict conversion to AD dementia and course of cognitive functioning in a MCI sample with a high proportion of early-stage MCI patients. Methods: Variables known to predict progression in MCI patients and hypothesized to predict progression in early-stage MCI patients were selected. Cognitive (long-delay free recall, regional primacy score), imaging (hippocampal …and entorhinal cortex volumes, fornix fractional anisotropy), and CSF (Aβ1–42 /t-tau, Aβ1–42 ) variables from 36 MCI patients were analyzed with Cox regression and mixed-effect models to determine their individual and combined abilities to predict time to conversion to AD dementia and course of global cognitive functioning, respectively. Results: Those variables hypothesized to predict the course of early-stage MCI patients were most predictive for MCI progression. Specifically, regional primacy score (a measure of word-list position learning) most consistently predicted conversion to AD dementia and course of cognitive functioning. Both the prediction of conversion and course of cognitive functioning were maximized by including CSF Aβ1–42 and fornix integrity biomarkers, respectively, indicating the complementary information carried by cognitive variables and biomarkers. Conclusion: Predictors of MCI progression need to be interpreted in light of the characteristics of the respective MCI sample. Future studies should aim to compare predictive strengths of markers between early-stage and late-stage MCI patients. Show more

Keywords: Alzheimer's disease, amyloid, cerebrospinal fluid, dementia, diffusion tensor imaging, fornix (brain), magnetic resonance imaging, memory, mild cognitive impairment

DOI: 10.3233/JAD-141716

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 625-633, 2015

Authors: Möller, Christiane | Dieleman, Nikki | van der Flier, Wiesje M. | Versteeg, Adriaan | Pijnenburg, Yolande | Scheltens, Philip | Barkhof, Frederik | Vrenken, Hugo

Article Type: Research Article

Abstract: Background: The involvement of frontostriatal circuits in frontotemporal dementia (FTD) suggests that deep gray matter structures (DGM) may be affected in this disease. Objective: We investigated whether volumes of DGM structures differed between patients with behavioral variant FTD (bvFTD), Alzheimer's disease (AD), and subjective complaints (SC) and explored relationships between DGM structures, cognition, and neuropsychiatric functioning. Methods: For this cross-sectional study, we included 24 patients with FTD and matched them based on age, gender, and education at a ratio of 1:3 to 72 AD patients and 72 patients with SC who served as controls. Volumes of …hippocampus, amygdala, thalamus, caudate nucleus, putamen, globus pallidus, and nucleus accumbens were estimated by automated segmentation of 3D T1-weighted MRI. MANOVA with Bonferroni adjusted post-hoc tests was used to compare volumes between groups. Relationships between volumes, cognition, and neuropsychiatric functioning were examined using multivariate linear regression and Spearman correlations. Results: Nucleus accumbens and caudate nucleus discriminated all groups, with most severe atrophy in FTD. Globus pallidus volumes were smallest in FTD and discriminated FTD from AD and SC. Hippocampus, amygdala, thalamus, and putamen were smaller in both dementia groups compared to SC. Associations between amygdala and memory were found to be different in AD and FTD. Globus pallidus and nucleus accumbens were related to attention and executive functioning in FTD. Conclusion: Nucleus accumbens, caudate nucleus, and globus pallidus were more severely affected in FTD than in AD and SC. The associations between cognition and DGM structures varied between the diagnostic groups. The observed difference in volume of these DGM structures supports the idea that next to frontal cortical atrophy, DGM structures, as parts of the frontal circuits, are damaged in FTD rather than in AD. Show more

Keywords: Alzheimer's disease, atrophy, basal ganglia, frontotemporal dementia

DOI: 10.3233/JAD-141230

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 635-647, 2015

Authors: Mangialasche, Francesca | Baglioni, Mauro | Cecchetti, Roberta | Kivipelto, Miia | Ruggiero, Carmelinda | Piobbico, Danilo | Kussmaul, Lothar | Monastero, Roberto | Brancorsini, Stefano | Mecocci, Patrizia

Article Type: Research Article

Abstract: Background: Specific mechanisms behind the role of oxidative/nitrosative stress and mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis remain elusive. Mitochondrial aconitase (ACO2) is a Krebs cycle enzyme sensitive to free radical-mediated damage. Objective: We assessed activity and expression of ACO2 extracted from blood lymphocytes of subjects with AD, mild cognitive impairment (MCI), older adults with normal cognition (OCN, age ≥65 years), and younger adults with normal cognition (YCN, age <65 years). Plasma levels and activities of antioxidants were also measured. Methods: Blood samples were collected from 28 subjects with AD, 22 with MCI, 21 OCN, and …19 YCN. ACO2 activity was evaluated in a subsample before and after in vitro exposure to free radicals. Results: ACO2 activity was significantly lower in AD and MCI cases than controls: ACO2 median activity was 0.64 ± 0.21 U/mg protein for AD, 0.93 ± 0.28 U/mg protein for MCI, 1.17 ± 0.78 U/mg protein for OCN subjects, and 1.23 ± 0.43 U/mg protein for YCN individuals. In subjects with AD and MCI, ACO2 expression was lower than OCN subjects, and ACO2 activity correlated with vitamin E plasma levels (rho: 0.64, p < 0.001) and Mini-Mental State Examination total score (rho: 0.82, p < 0.001). Furthermore, free radicals exposure reduced ACO2 activity more in individuals with AD than in OCN subjects. Conclusion: Our results suggest that ACO2 activity is reduced in peripheral lymphocytes of subjects with AD and MCI and correlates with antioxidant protection. Further studies are warranted to verify the role of ACO2 in AD pathogenesis and its importance as a marker of AD progression. Show more

Keywords: Aconitase (aconitate hydratase), Alzheimer disease, antioxidants, free radicals, lymphocyte, mild cognitive impairment, mitochondria, oxidative stress, reactive nitrogen species, reactive oxygen species

DOI: 10.3233/JAD-142052

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 649-660, 2015

Authors: Park, Hee Kyung | Choi, Seong Hye | Park, Sun A. | Kim, Hwa Jung | Lee, Yunhwan | Han, Seol-Heui | Kim, Eun-Joo | Kim, Byeong C. | Han, Hyun Jeoung | Moon, So Young | Yang, Dong Won | Park, Kyung Won | Park, Kee Hyung | Yoon, Bora | Seo, Sang Won | Na, Duk L. | Na, Hae Ri | Lee, Jae-Hong

Article Type: Research Article

Abstract: Background & Objective: Early-onset Alzheimer's disease (EOAD, onset age < 65 years) may differ from late-onset Alzheimer's disease (LOAD) in terms of cognitive profiles and neuropsychiatric symptoms. There have been few studies for Korean EOAD patients using well-structured databases. Previous studies focusing on cognitive profiles between the two groups had a variety of demographic data and comparability. The purpose of this study was to identify the unique profiles of cognitive functions and neuropsychiatric symptoms in Korean EOAD patients that differentiate from LOAD. Methods: Through propensity score matching, a total of 435 patients with EOAD and a total of …435 patients with LOAD were included in this nationwide, multicenter, hospital-based study. Each patient underwent comprehensive neurological examination, interview for caregiver, neuropsychological tests, and brain magnetic resonance imaging. Results: Neuropsychological test results showed worse performances on frontal/executive functions, visuospatial function, and visual memory in EOAD patients as compared to LOAD patients. In terms of neuropsychiatric symptoms, apathy was more common in EOAD patients, while delusions were more prevalent in LOAD patients. The differences in neuropsychiatric symptoms between the two groups were most pronounced in patients with the APOE ε4 allele, suggesting that neuropsychiatric symptoms in AD may be influenced by the APOE genotype. Conclusion: Our results suggested that EOAD may be an important phenotype, fronto-parietal dysfunction, in the spectrum of AD, and this finding can provide for early diagnosis of EOAD patients. Show more

Keywords: Alzheimer's disease, APOE genotype, early-onset dementia, nulticenter study

DOI: 10.3233/JAD-141011

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 661-673, 2015

Authors: König, Alexandra | Crispim Junior, Carlos Fernando | Derreumaux, Alexandre | Bensadoun, Gregory | Petit, Pierre-David | Bremond, François | David, Renaud | Verhey, Frans | Aalten, Pauline | Robert, Philippe

Article Type: Research Article

Abstract: Over the last few years, the use of new technologies for the support of elderly people and in particular dementia patients received increasing interest. We investigated the use of a video monitoring system for automatic event recognition for the assessment of instrumental activities of daily living (IADL) in dementia patients. Participants (19 healthy subjects (HC) and 19 mild cognitive impairment (MCI) patients) had to carry out a standardized scenario consisting of several IADLs such as making a phone call while they were recorded by 2D video cameras. After the recording session, data was processed by a platform of video signal …analysis in order to extract kinematic parameters detecting activities undertaken by the participant. We compared our automated activity quality prediction as well as cognitive health prediction with direct observation annotation and neuropsychological assessment scores. With a sensitivity of 85.31% and a precision of 75.90%, the overall activities were correctly automatically detected. Activity frequency differed significantly between MCI and HC participants (p < 0.05). In all activities, differences in the execution time could be identified in the manually and automatically extracted data. We obtained statistically significant correlations between manually as automatically extracted parameters and neuropsychological test scores (p < 0.05). However, no significant differences were found between the groups according to the IADL scale. The results suggest that it is possible to assess IADL functioning with the help of an automatic video monitoring system and that even based on the extracted data, significant group differences can be obtained. Show more

Keywords: Alzheimer's disease, assessment, autonomy, dementia, mild cognitive impairment, information and communication technologies, instrumental activities of daily living, video analyses

DOI: 10.3233/JAD-141767

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 675-685, 2015

Authors: Ravona-Springer, Ramit | Haratz, Salo | Tanne, David | Schmeidler, James | Efrati, Shai | Rosendorff, Clive | Beeri, Michal Schnaider | Silverman, Jeremy M.

Article Type: Research Article

Abstract: Regression analyses compared 41 type 2 diabetes (T2D) and 131 non-T2D cognitively normal elderly males on the associations of arterial wall function measures [large artery elasticity index (LAEI), small artery elasticity index (SAEI), systemic vascular resistance (SVR), and total vascular impedance (TVI)] with cognitive performance (memory, language, and executive functions), controlling for socio-demographic and cardiovascular factors. Higher LAEI and lower TVI were significantly associated with better executive functions performance in T2D but not in non-T2D subjects. Lower TVI was more associated with better language performance in T2D. Results suggest that arterial wall function is associated with cognition in T2D.

Keywords: Arterial wall function, cognitive function, large artery elasticity index, total vascular impedance, type 2 diabetes

DOI: 10.3233/JAD-141197

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 687-693, 2015

Authors: Casado Naranjo, Ignacio | Portilla Cuenca, Juan Carlos | Duque de San Juan, Beatriz | García, Alfonso Falcón | Sevilla, Raúl Romero | Serrano Cabrera, Ana | Hijón, Carmen Cámara | Romero Chala, Silvia | Fuentes, José Manuel | Ramírez Moreno, José María

Article Type: Research Article

Abstract: Background and objective: Current evidence shows that numerous classic vascular risk factors (VRF) contribute to mild cognitive impairment (MCI), but the effects of emerging VRFs are less well-known. Using a comprehensive approach, we assessed the frequency and strength of association between MCI and classic VRFs, subclinical markers of atherosclerosis (cystatin C, lipoprotein(a), high-sensitivity C-reactive protein, and intima-media thickness) and white matter hyperintensities (WMH). Methods: In this case-control study of consecutive MCI patients and cognitively normal controls, subjects underwent clinical and neuropsychological examinations, laboratory analyses, a carotid duplex scan, and a brain magnetic resonance imaging scan. Results: …The study included 105 patients with amnestic MCI (aMCI): 24 with single domain amnestic MCI, 81 with multiple domain amnestic MCI, and 76 controls. Compared to controls, patients with aMCI were significantly older and had higher rates of arterial hypertension, atrial fibrillation, and depression. They also had a larger intima-media thickness and higher load of WMHs, both periventricular (WMHpv) and subcortical (WMHsc). In the adjusted analysis, all variables except WMHsc displayed a significant association with aMCI. Body mass index exerted a protective effect. Conclusions: Our findings suggest a direct association between aMCI and age, hypertension, atrial fibrillation depression, intima-media thickness, and WMHpv. Body mass index has a protective effect on this MCI subtype. Show more

Keywords: Atherosclerosis, carotid intima-media thickness, mild cognitive impairment, vascular risk factors, white matter hyperintensities

DOI: 10.3233/JAD-141770

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 695-704, 2015

Authors: Wischik, Claude M. | Staff, Roger T. | Wischik, Damon J. | Bentham, Peter | Murray, Alison D. | Storey, John M.D. | Kook, Karin A. | Harrington, Charles R.

Article Type: Short Communication

Abstract: Background: As tau aggregation pathology correlates with clinical dementia in Alzheimer's disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. Methods: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer's Disease Assessment Scale-cognitive subscale …(ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6- and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333). Results: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: −5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations. Conclusion: The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD. Show more

Keywords: Alzheimer's disease, controlled clinical trial, intervention studies, methylthioninium, safety, tau protein

DOI: 10.3233/JAD-142874

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 705-720, 2015

Article Type: Other

DOI: 10.3233/JAD-141771

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 721-723, 2015