Journal of Alzheimer's Disease - Volume 58, issue 3

Authors: Snow, Wanda M. | Dale, Ryan | O’Brien-Moran, Zoe | Buist, Richard | Peirson, Danial | Martin, Melanie | Albensi, Benedict C.

Article Type: Research Article

Abstract: A diagnosis of Alzheimer’s disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo . Its utility in …AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both Aβ plaques and neurofibrillary tangles. Mean diffusivity did not differ between 3xTg and control mice in any region. Decreased fractional anisotropy (p  < 0.01) and axial diffusivity (p  < 0.05) were detected only in the hippocampus, in which both congophilic Aβ plaques and hyperphosphorylated tau accumulation, consistent with neurofibrillary tangle formation, were detected. Pathological tau accumulation was seen in the cortex. The entorhinal cortex was largely spared from AD-related neuropathology. This is the first study to demonstrate DTI abnormalities in gray matter in a mouse model of AD in which both pathological hallmarks are present, suggesting the feasibility of DTI as a non-invasive means of detecting brain pathology in vivo in early-stage AD. Show more

Keywords: 3xTg, Alzheimer’s disease, diffusion tensor imaging, gray matter, hippocampus, neurofibrillary tangles

DOI: 10.3233/JAD-170136

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 841-853, 2017

Authors: Tort-Merino, Adrià | Valech, Natalia | Peñaloza, Claudia | Grönholm-Nyman, Petra | León, María | Olives, Jaume | Estanga, Ainara | Ecay-Torres, Mirian | Fortea, Juan | Martínez-Lage, Pablo | Molinuevo, José L. | Laine, Matti | Rodríguez-Fornells, Antoni | Rami, Lorena

Article Type: Research Article

Abstract: We employed a highly demanding experimental associative learning test (the AFE-T) to explore memory functioning in Preclinical Alzheimer’s Disease stage 1 (PreAD-1) and stage 2 (PreAD-2). The task consisted in the learning of unknown object/name pairs and our comprehensive setup allowed the analysis of learning curves, immediate recall, long-term forgetting rates at one week, three months, and six months, and relearning curves. Forty-nine cognitively healthy subjects were included and classified according to the presence or absence of abnormal CSF biomarkers (Control, n  = 31; PreAD-1, n  = 14; PreAD-2, n  = 4). Control and PreAD-1 performances on the experimental test were compared by …controlling for age and education. These analyses showed clear learning difficulties in PreAD-1 subjects (F = 6.98; p  = 0.01). Between-group differences in long-term forgetting rates were less notable, reaching statistical significance only for the three-month cued forgetting rate (F = 4.83; p  = 0.03). Similarly, relearning sessions showed only statistical trends between the groups (F = 3.22; p  = 0.08). In the whole sample, significant correlations between CSF Aβ42 /tau ratio and the AFE-T were found, both in the total learning score (r  = 0.52; p  < 0.001) and in the three-month cued forgetting rate (r  = –0.38; p  < 0.01). Descriptive subanalyses involving PreAD-2 suggested greater learning and recall difficulties in these subjects when compared with the PreAD-1 group. The present results suggest that explicit learning difficulties when binding information could be one of the earliest signs of the future emergence of episodic memory difficulties on the Alzheimer’s disease continuum. Our findings indicate that the AFE-T is a sensitive test, capable of detecting subtle memory difficulties in PreAD-1. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive aging, memory, neuropsychology

DOI: 10.3233/JAD-161173

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 855-870, 2017

Authors: Laughlin, Gail A. | Kritz-Silverstein, Donna | Bergstrom, Jaclyn | Reas, Emilie T. | Jassal, Simerjot K. | Barrett-Connor, Elizabeth | McEvoy, Linda K.

Article Type: Research Article

Abstract: Background: Evidence of a role for vitamin D (VitD) in cognitive aging is mixed and based primarily on extreme VitD deficiency. We evaluated the association of VitD insufficiency with cognitive function in older, community-dwelling adults living in a temperate climate with year-round sunshine. Methods: A population-based longitudinal study of 1,058 adults (median age 75; 62% women) who had cognitive function assessed and serum levels of 25-hydroxyvitaminD (25OHD) measured in 1997–99 and were followed for up to three additional cognitive function assessments over a 12-year period. Results: Overall, 14% (n  = 145) of participants had VitD insufficiency …defined as 25OHD <30 ng/ml. Adjusting for age, sex, education, and season, VitD insufficiency was associated with poorer baseline performance on the Mini-Mental Status Exam (MMSE) (p  = 0.013), Trails Making Test B (Trails B) (p  = 0.015), Category Fluency (p  = 0.006), and Long Term Retrieval (p  = 0.019); differences were equivalent to 5 years of age. For those with VitD insufficiency, the odds of mildly impaired performance at baseline were 38% higher for MMSE (p  = 0.08), 78% higher for Trails B (p  = 0.017), and 2-fold higher for Category Fluency and Long Term Retrieval (both p  = 0.001). VitD insufficiency was not related to the rate of cognitive decline on any test or the risk of developing impaired performance during follow-up. Conclusion: In this population with little VitD deficiency, even moderately low VitD was associated with poorer performance on multiple domains of cognitive function. Low VitD did not predict 12-year cognitive decline. Clinical trials are essential to establish a causal link between VitD and cognitive well-being. Show more

Keywords: Cognitive aging, cognitive function, epidemiology, longitudinal study, vitamin D

DOI: 10.3233/JAD-161295

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 871-883, 2017

Authors: Suridjan, Ivonne | Herrmann, Nathan | Adibfar, Alex | Saleem, Mahwesh | Andreazza, Ana | Oh, Paul I. | Lanctôt, Krista L.

Article Type: Research Article

Abstract: This study examined associations between lipid peroxidation markers and cognition, and associations between these markers and cognitive response to an exercise intervention program, in adults with coronary artery disease at risk of dementia. Lipid peroxidation products were measured in serum in 118 patients (29 possible vascular mild cognitive impairment and 89 controls). Ratios of early- (lipid hydroperoxides, LPH) to late-stage (8-isoprostane, 8-ISO; 4-hydroxy-2-nonenal, 4-HNE) lipid peroxidation products were calculated. Cognitive performance was assessed before and at completion of a 24-week exercise intervention program. A global effect of group on lipid peroxidation markers was observed, adjusting for sex, years of education, …and cardiopulmonary fitness (main effect of group F (3,102) = 2.957, p  = 0.036). Lower lipid peroxidation at baseline, as determined by lower 8-ISO concentration, was associated with greater improvement in verbal memory (F (1, 64) = 4.738, p  = 0.03) and executive function (F (1, 64) = 5.219, p  = 0.026) performance. Similarly, higher ratios of 8-ISO/LPH (F (1, 65) = 6.592, p  = 0.013) and (8-ISO+4-HNE) to LPH (F (1, 65) = 3.857, p  = 0.054), were associated with less improvement in executive function performance over a 24-week exercise intervention. Lipid peroxidation may be a biomarker of early vascular cognitive impairment, and elevated lipid peroxidation might limit the cognitive benefits of exercise in this high-risk population. Show more

Keywords: Cardiovascular, coronary artery disease, exercise, heart disease, hydroperoxide, hydroxynonenal, isoprostane, lipid peroxidation, oxidative stress, vascular cognitive impairment

DOI: 10.3233/JAD-161248

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 885-896, 2017

Authors: Sun, Hongbing

Article Type: Research Article

Abstract: Background: Associations between environmental factors and spatial disparity of mortality rates of Alzheimer’s disease (AD) in the US are not well understood. Objective: To find associations between 41 trace elements, four common risk factors, and AD mortality rates in the48 contiguous states. Methods: Isopleth maps of AD mortality rates of the 48 states and associated factors were examined. Correlations between state average AD mortality rates and concentrations of 41 soil elements, wine consumption, percentage of current smokers, obesity, and diagnosed diabetes of the 48 states between 1999 and 2014 were analyzed. Results: Among …41 elements, soil selenium concentrations have the most significant inverse correlations with AD mortality rates. Rate ratio (RR) of the 6 states with the lowest product of soil selenium and sulfur concentrations is 53% higher than the 6 states with the highest soil selenium sulfur product in the 48 states (RR = 1.53, CI95% 1.51–1.54). Soil tin concentrations have the most significant inverse correlation with AD mortality growth rates between 1999 and 2014, followed by soil sulfur concentrations. Percentages of obesity, diagnosed diabetes, smoking, and wine consumption per capita also correlate significantly with AD mortality growth rates. Conclusions: High soil selenium and sulfur concentrations and wine consumption are associated with low AD mortality rates. Given that average soil selenium and sulfur concentrations are indicators of their intakes from food, water, and air by people in a region, long-term exposure to high soil selenium and sulfur concentrations might be beneficial to AD mortality rate reduction in a region. Show more

Keywords: Alzheimer’s disease, soil selenium, spatial disparity, sulfur, tin

DOI: 10.3233/JAD-170059

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 897-907, 2017

Authors: Sala, Isabel | Illán-Gala, Ignacio | Alcolea, Daniel | Sánchez-Saudinós, Ma Belén | Salgado, Sergio Andrés | Morenas-Rodríguez, Estrella | Subirana, Andrea | Videla, Laura | Clarimón, Jordi | Carmona-Iragui, María | Ribosa-Nogué, Roser | Blesa, Rafael | Fortea, Juan | Lleó, Alberto

Article Type: Research Article

Abstract: Background: Episodic memory impairment is the core feature of typical Alzheimer’s disease. Objective: To evaluate the performance of two commonly used verbal memory tests to detect mild cognitive impairment due to Alzheimer’s disease (MCI-AD) and to predict progression to Alzheimer’s disease dementia (AD-d). Methods: Prospective study of MCI patients in a tertiary memory disorder unit. Patients underwent an extensive neuropsychological battery including two tests of declarative verbal memory: The Free and Cued Selective Reminding Test (FCSRT) and the word list learning task from the Consortium to Establish a Registry for Alzheimer’s disease (CERAD-WL). Cerebrospinal fluid …(CSF) was obtained from all patients and MCI-AD was defined by means of the t-Tau/Aβ1–42 ratio. Logistic regression analyses tested whether the combination of FCSRT and CERAD-WL measures significantly improved the prediction of MCI-AD. Progression to AD-d was analyzed in a Cox regression model. Results: A total of 202 MCI patients with a mean follow-up of 34.2±24.2 months were included and 98 (48.5%) met the criteria for MCI-AD. The combination of FCSRT and CERAD-WL measures improved MCI-AD classification accuracy based on CSF biomarkers. Both tests yielded similar global predictive values (59.9–65.3% and 59.4–62.8% for FCSRT and CERAD-WL, respectively). MCI-AD patients with deficits in both FCSRT and CERAD-WL had a faster progression to AD-d than patients with deficits in only one test. Conclusions: The combination of FCSRT and CERAD-WL improves the classification of MCI-AD and defines different prognostic profiles. These findings have important implications for clinical practice and the design of clinical trials. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, episodic memory, mild cognitive impairment, mild neurocognitive disorder, neuropsychological test

DOI: 10.3233/JAD-170073

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 909-918, 2017

Authors: Jin, Wang-Sheng | Bu, Xian-Le | Wang, Ye-Ran | Li, Ling | Li, Wei-Wei | Liu, Yu-Hui | Zhu, Chi | Yao, Xiu-Qing | Chen, Yang | Gao, Chang-Yue | Zhang, Tao | Zhou, Hua-Dong | Zeng, Fan | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Previous studies have suggested that cardiovascular functions might play a critical role in Alzheimer’s disease (AD) pathogenesis. However, the relationship among heart function, blood flow of cerebral vessels, and AD remains unclear. In the present study, AD patients (n  = 34) and age- and gender-matched cognitively normal controls (n  = 34) were recruited. Demographic and comorbidity information was collected. The ejection fraction was measured using echocardiography, and the mean velocity, pulsatility index (PI), and resistance index (RI) of the basilar artery (BA), left terminal internal carotid artery (LTICA), and right terminal internal carotid artery (RTICA) were measured using transcranial Doppler. The data …of lacunae, white matter changes, and plaques in the aortic arch and carotid arteries were collected from brain magnetic resonance imaging and computed tomography angiography images. Compared with normal controls, AD patients had lower ejection fractions and cerebral blood flow velocities and higher RI and PI in the BA, LTICA, and RTICA, as well as more plaques in the aortic and carotid arteries. In the multivariate logistic regression analysis, the ejection fraction and the mean velocity of the BA and LTICA were independently associated with AD after adjusting for age, gender, education, vascular risk factors, arterial plaques, and brain ischemic lesions detected in the brain images. These findings suggest that heart function and vascular condition may play important roles in AD pathogenesis. Improving cardiovascular functions could be a promising approach for the prevention and treatment of AD. Show more

Keywords: Alzheimer’s disease, cerebral blood flow, ejection fractions, heart

DOI: 10.3233/JAD-170088

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 919-925, 2017

Authors: Lu, Hanna | Chan, Sandra S.M. | Fung, Ada W.T. | Lam, Linda C.W.

Article Type: Research Article

Abstract: Background: Processing speed has been highlighted as a diagnostic item for neurocognitive disorders (NCD) in DSM-5. The utility of information processing speed (IPS) enclosed with multiscale constructs in the diagnosis of NCD warrants exploration. Objective: We aimed to investigate the IPS with two types of measurements in the patients with NCD due to vascular disease (NCD-vascular) and NCD due to Alzheimer’s disease (NCD-AD), and examine the associations between IPS measures and morphometric features. Methods: The IPS was evaluated using trail making test (TMT) and flanker test (n  = 204). Direct scores, derived scores, and reaction time …(RT) were used as IPS measures. Further, surface-based morphometry cortical volume was calculated in a subsample (n  = 44) with structural MRI data. Results: All IPS measures showed a significant value to differentiate NCD patients from healthy subjects. Only mean RT could distinguish NCD-AD from NCD-vascular groups. TMT-B score and difference score were correlated with gray matter volume (GMV) of inferior frontal gyrus, precuneus and superior temporal cortex. Mean RT was associated with the GMV of post-central gyrus (r  = –0.327, p  = 0.035), and executive speed was associated with inferior frontal cortex (r  = –0.475, p  = 0.001), cingulate gyrus (r  = –0.497, p  = 0.001), and superior temporal gyrus (r  = –0.36, p  = 0.019). Conclusion: The cognitive and morphometric correlates of IPS measures indicate that complex IPS might be decomposed into the domain-specific components with corresponding neural underpinnings. Our findings may also provide essential insights into the diagnostic item of NCD. Show more

Keywords: Gray matter volume, information processing speed, morphometry, neurocognitive disorders, reaction time, trail making test

DOI: 10.3233/JAD-161122

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 927-937, 2017

Authors: Wolfsgruber, Steffen | Polcher, Alexandra | Koppara, Alexander | Kleineidam, Luca | Frölich, Lutz | Peters, Oliver | Hüll, Michael | Rüther, Eckart | Wiltfang, Jens | Maier, Wolfgang | Kornhuber, Johannes | Lewczuk, Piotr | Jessen, Frank | Wagner, Michael

Article Type: Research Article

Abstract: Background: There is very limited data on the prevalence of abnormal cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) and their predictive value for clinical progression in memory clinic patients with subjective cognitive decline (SCD). Objective: To assess the frequency of abnormal CSF biomarkers of AD and their predictive value for clinical progression in memory clinic patients with SCD in comparison to patients with mild cognitive impairment (MCI) from the same cohort. Methods: We analyzed prospective data from memory clinic patients of the German Competence Network Dementia cohort with a baseline diagnosis of SCD (n … = 82) or MCI (n  = 134), distinguished by actuarial neuropsychological MCI criteria (“Jak-Bondi criteria”). Risk of clinical progression during 3-year follow-up was evaluated with Cox-Proportional-Hazard models. Results: Prevalence of abnormal values in CSF markers of tau-mediated neurodegeneration (67.8% versus 46.3%) but not of amyloid deposition (40.3% versus 35.4%) was significantly higher in MCI compared to SCD. The rate of incident AD dementia (26.1% versus 12.2%) was also significantly higher in MCI. In SCD, additional 22% progressed to MCI during follow-up. Combined amyloid/tau abnormality was the strongest predictor of clinical progression in both groups. Conclusion: High prevalence of biomarker abnormality and clinical progression, together with the predictive value of CSF biomarkers, in memory clinic patients with SCD support the validity and usefulness of this condition as a “pre-MCI” at risk stage of AD. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-161252

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 939-950, 2017

Authors: Mowrey, Wenzhu B. | Lipton, Richard B. | Katz, Mindy J. | Ramratan, Wendy S. | Loewenstein, David A. | Zimmerman, Molly E. | Buschke, Herman

Article Type: Correction

DOI: 10.3233/JAD-179003

Citation: Journal of Alzheimer's Disease, vol. 58, no. 3, pp. 951-952, 2017