Journal of Alzheimer's Disease - Volume 49, issue 2

Authors: Bensamoun, David | Guignard, Renaud | Furst, Ansgar J. | Derreumaux, Alexandre | Manera, Valeria | Darcourt, Jacques | Benoit, Michel | Robert, Philippe H. | David, Renaud

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect the majority of patients with dementia, and result in a greater cognitive and functional impairment. Objective: To investigate associations between BPSD and amyloid cerebral deposition as measured by 18 F-Florbetapir-PET quantitative uptake in elderly subjects with and without cognitive impairment. Methods: Participants with cognitive impairment [mild cognitive impairment (MCI) or Alzheimer’s disease (AD)] and healthy controls (HC) from the ADNI cohort (Alzheimer Disease Neuroimaging Initiative) who underwent an 18 F-florbetapir PET scan between May 2010 and March 2014 were included. Clinical assessments …included the Clinical Dementia Rating, the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Freesurfer software was used to extract PET counts based on T1-based structural ROI (frontal, cingulate, parietal, and temporal). Spearman’s partial correlation scores between BPSD severity and regional amyloid uptake were calculated. Results: Data for 657 participants [age = 72.6 (7.19); MMSE = 27.4 (2.67)] were analyzed, including 230 HC [age = 73.1 (6.02); MMSE = 29 (1.21)], 308 MCI [age = 71.5 (7.44); MMSE = 28.0 (1.75)], and 119 AD subjects [age = 74.7 (8.05); MMSE = 23.1 (2.08)]. Considering all diagnostic groups together, positive significant correlations were found between anxiety and 18 F-florbetapir uptake in the frontal (r  = 0.102; p  = 0.009), cingulate (r  = 0.083; p  = 0.034), and global cerebral uptake (r  = 0.099; p  = 0.011); between irritability and frontal (r  = 0.089; p  = 0.023), cingulate (r  = 0.085; p  = 0.030), parietal (r  = 0.087; p  = 0.025), and global cerebral uptake (r  = 0.093; p  = 0.017); in the MCI subgroup, between anxiety and frontal (r  = 0.126; p  = 0.03) and global uptake (r  = 0.14; p  = 0.013); in the AD subgroup, between irritability and parietal uptake (r  = 0.201; p  = 0.03). Conclusion: Anxiety and irritability are associated with greater amyloid deposition in the neurodegenerative process leading to AD. Show more

Keywords: ADNI, Alzheimer’s disease, amyloid, anxiety, behavioral and psychological symptoms of dementia, dementia, cingulate, frontal, irritability, neuroimaging, neuropsychiatric symptoms

DOI: 10.3233/JAD-150181

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 387-398, 2016

Authors: Shi, Zhongyong | Zhu, Yingbo | Wang, Meijuan | Wu, Yujie | Cao, Jing | Li, Chunbo | Xie, Zhongcong | Shen, Yuan

Article Type: Research Article

Abstract: Our previous studies have shown that longitudinal reduction in retinal nerve fiber layer (RNFL) thickness is associated with cognitive deterioration. However, whether the combination of longitudinal reduction in RNFL thickness with baseline episodic memory performance can better predict cognitive deterioration remains unknown. Therefore, we set out to re-analyze the data obtained from our previous studies with 78 elderly adults (mean age 74.4 ± 3.83 years, 48.7% male) in the community over a 25-month period. The participants were categorized as either stable participants whose cognitive status did not change (n  = 60) or converted participants whose cognitive status deteriorated (n  = 18). A …logistic regression analysis was applied to determine a conversion score for predicting the cognitive deterioration in the participants. We found that the area under the receiver operating characteristic curve (AUC) for the multivariable model was 0.854 (95% CI 0.762–0.947) using baseline story recall as a predictor, but the AUC increased to 0.915 (95% CI 0.849–0.981) with the addition of the longitudinal reduction of RNFL thickness in the inferior quadrant. The conversion score was significantly higher for the converted participants than the stable participants (0.59 ± 0.30 versus 0.12 ± 0.19, p  <  0.001). Finally, the optimal cutoff value of the conversion score (0.134) was determined by the analysis of receiver operating characteristic curve, and this conversion score generated a sensitivity of 0.944 and a specificity of 0.767 in predicting the cognitive deterioration. These findings have established a system to perform a larger scale study to further test whether the longitudinal reduction in RNFL thickness could serve as a biomarker of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, conversion score, mild cognitive impairment, predictive model, retinal nerve fiber layer thickness

DOI: 10.3233/JAD-150438

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 399-405, 2016

Authors: Fraser, Kathleen C. | Meltzer, Jed A. | Rudzicz, Frank

Article Type: Research Article

Abstract: Background: Although memory impairment is the main symptom of Alzheimer’s disease (AD), language impairment can be an important marker. Relatively few studies of language in AD quantify the impairments in connected speech using computational techniques. Objective: We aim to demonstrate state-of-the-art accuracy in automatically identifying Alzheimer’s disease from short narrative samples elicited with a picture description task, and to uncover the salient linguistic factors with a statistical factor analysis. Methods: Data are derived from the DementiaBank corpus, from which 167 patients diagnosed with “possible” or “probable” AD provide 240 narrative samples, and 97 controls provide an …additional 233. We compute a number of linguistic variables from the transcripts, and acoustic variables from the associated audio files, and use these variables to train a machine learning classifier to distinguish between participants with AD and healthy controls. To examine the degree of heterogeneity of linguistic impairments in AD, we follow an exploratory factor analysis on these measures of speech and language with an oblique promax rotation, and provide interpretation for the resulting factors. Results: We obtain state-of-the-art classification accuracies of over 81% in distinguishing individuals with AD from those without based on short samples of their language on a picture description task. Four clear factors emerge: semantic impairment, acoustic abnormality, syntactic impairment, and information impairment. Conclusion: Modern machine learning and linguistic analysis will be increasingly useful in assessment and clustering of suspected AD. Show more

Keywords: Automatic data processing, factor analysis, geriatric assessment, heterogeneity, language, statistical

DOI: 10.3233/JAD-150520

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 407-422, 2016

Authors: Mehta, Hemalkumar B. | Mehta, Vinay | Tsai, Chu-Lin | Chen, Hua | Aparasu, Rajender R. | Johnson, Michael L.

Article Type: Research Article

Abstract: Background: Elderly patients with type 2 diabetes mellitus and hypertension are at high risk for developing dementia. In addition to comorbid disease conditions (Dx), prescription drugs (Rx) are important risk factors for dementia. Objective: Develop and validate the RxDx-Dementia risk index by combining diagnosis and prescription information in a single risk index to predict incident dementia, and compare its performance with diagnosis-based Charlson comorbidity score (CCS) and prescription-based chronic disease score (CDS). Methods: Elderly patients diagnosed with type 2 diabetes mellitus and hypertension, and without prior dementia were identified from the Clinical Practice Research Datalink (2003–2012). …A Cox proportional hazard model was constructed to model the time to dementia by incorporating age, gender, and 31 RxDx disease conditions as independent variables. Points were assigned to risk factors to obtain summary risk score. Discrimination and calibration of the risk index were evaluated. Different risk indices were compared against RxDx-Dementia risk index using c-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results: Of 133,176 patients with type 2 diabetes mellitus and hypertension, 3.42% patients developed dementia.The c-statistics value for RxDx-Dementia risk index was 0.806 (95% CI, 0.799–0.812). Based on the c-statistics, NRI and IDI values, the RxDx-Dementia risk index performed better compared to CCS, CDS, and their combinations. Conclusion: The RxDx-Dementia risk index can be a useful tool to identify hypertensive and diabetic patients who are at high risk of developing dementia. This has implications for clinical management of patients with multiple comorbid conditions as well as risk adjustment for database studies. Show more

Keywords: Dementia, hypertension, prediction model, risk index, Type 2 diabetes

DOI: 10.3233/JAD-150466

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 423-432, 2016

Authors: Joussain, Pauline | Bessy, Marion | Fournel, Arnaud | Ferdenzi, Camille | Rouby, Catherine | Delphin-Combe, Floriane | Krolak-Salmon, Pierre | Bensafi, Moustafa

Article Type: Research Article

Abstract: Background: Studies of olfaction in Alzheimer’s disease (AD) mainly focused on deficits in odor detection and identification, with very few investigations of olfactory emotional changes and their consequences for hedonics. Objective: The aim of the present study was to characterize affective evaluations of odors in AD patients. Methods: To this end, 20 AD patients and 20 matched controls were tested. Participants were screened for odor detection and identification ability and then asked to rate the intensity, pleasantness, and edibility of 20 odorants. Results: Results showed that, overall, AD patients had lower detection ability and …perceived all odors as weaker than controls. As expected, they had lower identification ability on both cued and non-cued tasks. In addition, when smelling pleasant odors, patients had significantly lower hedonic ratings than controls (p  <  0.02), whereas no group difference was found for neutral or unpleasant odors (p  >  0.05 in both cases). Moreover, an analysis combining both intensity and pleasantness ratings showed that whereas intensity increased as a function of pleasantness and unpleasantness in controls, this quadratic relationship was not observed in AD patients. Conclusions: The study suggests that the simplest categorization criteria of odors (intensity and hedonic valence) are impaired in AD patients (especially for pleasant odors). Show more

Keywords: Alzheimer’s disease, emotion, intensity, olfaction, pleasantness

DOI: 10.3233/JAD-150332

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 433-441, 2016

Authors: Rusznák, Zoltán | Kim, Woojin Scott | Hsiao, Jen-Hsiang T. | Halliday, Glenda M. | Paxinos, George | Fu, YuHong

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) has long been linked to Alzheimer’s disease (AD). Using J20 mice, which express human AβPP with Swedish and Indiana mutations, we studied early pathological changes in the olfactory bulb. The presence of AβPP/amyloid-β (Aβ) was examined in mice aged 3 months (before the onset of hippocampal Aβ deposition) and over 5 months (when hippocampal Aβ deposits are present). The number of neurons, non-neurons, and proliferating cells was assessed using the isotropic fractionator method. Our results demonstrate that although AβPP is overexpressed in some of the mitral cells, widespread Aβ deposition and microglia aggregates are not …prevalent in the olfactory bulb. The olfactory bulbs of the younger J20 group harbored significantly fewer neurons than those of the age-matched wild-type mice (5.57±0.13 million versus 6.59±0.36 million neurons; p  = 0.011). In contrast, the number of proliferating cells was higher in the young J20 than in the wild-type group (i.e., 6617±425 versus 4455±623 cells; p  = 0.011). A significant increase in neurogenic activity was also observed in the younger J20 olfactory bulb. In conclusion, our results indicate that (1) neurons participating in the mouse olfactory function overexpress AβPP; (2) the cellular composition of the young J20 olfactory bulb is different from that of wild-type littermates; (3) these differences may reflect altered neurogenic activity and/or delayed development of the J20 olfactory system; and (4) AβPP/Aβ-associated pathological changes that take place in the J20 hippocampus and olfactory bulb are not identical. Show more

Keywords: Alzheimer’s disease, amyloid-β, olfactory bulb, neuronal number, proliferation, neurogenesis

DOI: 10.3233/JAD-150368

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 443-457, 2016

Authors: Díaz, Mario | Fabelo, Noemí | Casañas-Sánchez, Verónica | Marin, Raquel | Gómez, Tomás | Quinto-Alemany, David | Pérez, José A.

Article Type: Research Article

Abstract: Current evidence suggests that lipid homeostasis in the hippocampus is affected by different genetic, dietary, and hormonal factors, and that its deregulation may be associated with the onset and progression of Alzheimer’s disease (AD). However, the precise levels of influence of each of these factors and their potential interactions remain largely unknown, particularly during neurodegenerative processes. In the present study, we have performed multifactorial analyses of the combined effects of diets containing different doses of docosahexaenoic acid (DHA), estrogen status (ovariectomized animals receiving vehicle or 17β-estradiol), and genotype (wild-type or transgenic APP/PS1 mice) in hippocampal lipid profiles. We have observed …that the three factors affect lipid classes and fatty acid composition to different extents, and that strong interactions between these factors exist. The most aberrant lipid profiles were observed in APP/PS1 animals receiving DHA-poor diets and deprived of estrogens. Conversely, wild-type animals under a high-DHA diet and receiving estradiol exhibited a lipid profile that closely resembled that of the hippocampus of control animals. Interestingly, though the lipid signatures of APP/PS1 hippocampi markedly differed from wild-type, administration of a high-DHA diet in the presence of estrogens gave rise to a lipid profile that approached that of control animals. Paralleling changes in lipid composition, patterns of gene expression of enzymes involved in lipid biosynthesis were also altered and affected by combination of experimental factors. Overall, these results indicate that hippocampal lipid homeostasis is strongly affected by hormonal and dietary conditions, and that manipulation of these factors might be incorporated in AD therapeutics. Show more

Keywords: Alzheimer’s disease, docosahexaenoic acid, 17β-estradiol, hippocampal lipids, multifactor analyses

DOI: 10.3233/JAD-150470

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 459-481, 2016

Authors: Ye, Byoung Seok | Jang, Eun Young | Kim, Seong Yoon | Kim, Eun-Joo | Park, Sun Ah | Lee, Yunhwan | Hong, Chang Hyung | Choi, Seong Hye | Yoon, Bora | Yoon, Soo Jin | Na, Hae Ri | Lee, Jae-Hong | Jeong, Jee H. | Kim, Hee Jin | Na, Duk L. | Seo, Sang Won

Article Type: Research Article

Abstract: Background and Objective: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients. Methods: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0–2.3 years), and risk of progression to probable Alzheimer’s disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and …decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value. Results: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07–3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49–0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41–3.72) and increased BMI (HR: 3.96, 95% CI: 2.62–6.00) groups were at increased risk of progression to pADD. Conclusions: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, body mass index, dementia, progression

DOI: 10.3233/JAD-150556

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 483-491, 2016

Authors: Berge, Guro | Lauridsen, Camilla | Sando, Sigrid Botne | Holder, Daniel Joseph | Møller, Ina | Aasly, Jan Olav | Bråthen, Geir | Savage, Mary Josephine | White, Linda Rosemary

Article Type: Research Article

Abstract: Background: There is substantial variation caused by preanalytical procedures in the measurement of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) reported in the literature. Objective: Determine whether the detergent Tween-20 improves diagnostic accuracy. Methods: CSF proteins (Aβ42 , Aβ40 , total tau, and phosphorylated tau) were measured by standard ELISA, in uncentrifuged CSF with or without 0.05% Tween-20 from patients with AD or amnestic mild cognitive impairment, and healthy elderly controls. In the main study, collection tubes containing Tween-20 (Sarstedt 15 mL) were filled with 5 mL CSF to ensure consistent detergent concentration across subsequent aliquots into …Corning 2 mL tubes. These latter were also the primary collection vessel for samples without Tween-20. The effect of centrifugation, and extra tube transfer of samples with Tween-20 were also examined. Results: 0.05% Tween-20 significantly increased mean measured CSF concentration of Aβ42 (30% ), Aβ40 (23% ), and total tau (4% ), but not phosphorylated tau. Generally, these increases were similar in all groups, although for Aβ42 , the mean percentage increase with Tween-20 was slightly larger for AD. Areas under receiver-operator characteristic curves were similar whether Tween-20 was present or not. Centrifuged CSF without Tween-20 significantly reduced the measured concentration of Aβ42 versus non-centrifuged samples, a difference not seen when detergent was added. Similar CSF Aβ42 levels were found whether Tween-20 was added at collection in an extra tube or directly to the main collection tube. Conclusion: Addition of Tween-20 to CSF did not improve differentiation of patients from controls. Show more

Keywords: Amyloid beta-peptides, dementia, human, synthetic detergent, tau protein

DOI: 10.3233/JAD-150234

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 493-502, 2016

Authors: Miwa, Kaori | Tanaka, Makiko | Okazaki, Shuhei | Yagita, Yoshiki | Sakaguchi, Manabu | Mochizuki, Hideki | Kitagawa, Kazuo

Article Type: Research Article

Abstract: Background: Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia. Objective: The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors. Methods: Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 μmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, …white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia. Results: In the 643 subjects (age: 67.2 ± 8.4 years, male: 59% ; education: 12.9 ± 2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2–13), 47 patients were diagnosed with dementia (Alzheimer’s disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE ɛ 4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p  = 0.043) and the highest tertile of tHcy (HR: 2.50, p  = 0.047) for all-cause dementia remained significant. Conclusions: Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk. Show more

Keywords: Alzheimer’s disease, cerebral small-vessel disease, dementia, estimated glomerular filtration rate, homocysteine, microbleeds, vascular dementia

DOI: 10.3233/JAD-150458

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 503-513, 2016