Journal of Alzheimer's Disease - Volume 49, issue 1

Authors: Spiegel, Jonathan | Pirraglia, Elizabeth | Osorio, Ricardo S. | Glodzik, Lidia | Li, Yi | Tsui, Wai | Saint Louis, Leslie A. | Randall, Catherine | Butler, Tracy | Xu, Jinfeng | Zinkowski, Raymond P. | Zetterberg, Henrik | Fortea, Juan | Fossati, Silvia | Wisniewski, Thomas | Davies, Peter | Blennow, Kaj | de Leon, Mony J.

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer’s disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, …P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD. Show more

Keywords: Alzheimer’s disease, biomarkers, hyperphosphorylated tau, P-tau181, P-tau231

DOI: 10.3233/JAD-150167

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 93-100, 2016

Authors: Savastano, Adriana | Klafki, Hans | Haußmann, Ute | Oberstein, Timo Jan | Muller, Petr | Wirths, Oliver | Wiltfang, Jens | Bayer, Thomas A.

Article Type: Research Article

Abstract: According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer’s disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβx-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβx-42 species appear to be the crucial players in AD etiology, the Aβ2-X isoforms did not receive much attention yet. …The present study is the first to show immunohistochemical evidence of Aβ2-X in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2. Show more

Keywords: 5XFAD, AβPP/PS1KI, Alzheimer’s disease, immunohistochemistry, mouse model, N-truncated Aβ, postmortem

DOI: 10.3233/JAD-150394

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 101-110, 2016

Authors: Clark, Camilla N. | Nicholas, Jennifer M. | Gordon, Elizabeth | Golden, Hannah L. | Cohen, Miriam H. | Woodward, Felix J. | Macpherson, Kirsty | Slattery, Catherine F. | Mummery, Catherine J. | Schott, Jonathan M. | Rohrer, Jonathan D. | Warren, Jason D.

Article Type: Research Article

Abstract: Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n  = 15), semantic dementia (SD; n  = 7), progressive nonfluent aphasia (PNFA; n  = 10), and Alzheimer’s disease (AD; n  = 16) versus healthy age-matched individuals (n  = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did …healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications. Show more

Keywords: Alzheimer’s disease, comedy, dementia, frontotemporal dementia, humor, progressive aphasia, semantic dementia

DOI: 10.3233/JAD-150413

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 111-119, 2016

Authors: Chan, Qun Lin | Xu, Xin | Shaik, Muhammad Amin | Chong, Steven Shih Tsze | Hui, Richard Jor Yeong | Chen, Christopher Li-Hsian | Dong, YanHong

Article Type: Research Article

Abstract: The informant AD8 has excellent discriminant ability for dementia case finding in tertiary healthcare settings. However, its clinical utility for dementia case finding at the forefront of dementia management, primary healthcare, is unknown. Therefore, we recruited participants from two primary healthcare centers in Singapore and measured their performance on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and a local formal neuropsychological battery, in addition to the AD8. Logistic regression was conducted to examine the associations between demographic factors and dementia. Area under the receiver operating characteristics (ROC) curve analysis was used to establish the …optimal cut-off points for dementia case finding. Of the 309 participants recruited, 243 (78.7%) had CDR = 0, 22 (7.1%) CDR = 0.5, and 44 (14.2%) CDR ≥1. Age was strongly associated with dementia, and the optimal age for dementia case finding in primary healthcare settings was ≥75 years. In this age group, the AD8 has excellent dementia case finding capability and was superior to the MMSE and equivalent to the MoCA [AD8 AUC (95% CI): 0.95 (0.91–0.99), cut-off: ≥3, sensitivity: 0.90, specificity: 0.88, PPV: 0.79 and NPV: 0.94; MMSE AUC (95% CI): 0.87 (0.79–0.94), p  = 0.04; MoCA AUC (95% CI): 0.88 (0.82–0.95), p  = 0.06]. In conclusion, the AD8 is well suited for dementia case finding in primary healthcare settings. Show more

Keywords: AD8, case finding, dementia, primary healthcare

DOI: 10.3233/JAD-150390

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 121-127, 2016

Authors: Li, Huajie | Zhu, Haihao | Wallack, Max | Mwamburi, Mkaya | Abdul-Hay, Samer O. | Leissring, Malcolm A. | Qiu, Wei Qiao

Article Type: Research Article

Abstract: Age is the major risk factor for developing Alzheimer’s disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-β peptide (Aβ) in plasma were measured. We further measured the activity of serum Aβ degradation by using fluorescein- and biotin-labeled Aβ40 . Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60–70, 70–80, and ≥80 years old. We found …that the older the subjects, the lower the concentration of insulin (p  = 0.001) and the higher the concentration of Aβ1-40 (p  = 0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aβ1-42 . These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aβ degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aβ40 are aging factors related to the risk of AD. Show more

Keywords: Aβ, Aβ degradation, age, Alzheimer’s disease, ApoE4, insulin

DOI: 10.3233/JAD-150428

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 129-137, 2016

Authors: Li, Fu-Dong | He, Fan | Chen, Ting-Rui | Xiao, Yuan-Yuan | Lin, Shang-Tong | Shen, Wei | Wang, Xin-Yi | Zhai, Yu-Jia | Shang, Xiao-Peng | Lin, Jun-Fen

Article Type: Research Article

Abstract: Background: Epidemiological studies suggest that proxies of higher lifetime estrogen exposure are associated with better cognitive function in postmenopausal women, but this has not been found consistently. Objective: To determine whether reproductive history, an important modifier of estrogen exposure across the lifetime, is associated with risk of cognitive impairment in postmenopausal women. Methods: We analyzed the baseline data from Zhejiang Major Public Health Surveillance Program (ZPHS) including 4,796 postmenopausal women. Cognitive impairment was assessed through the application of Mini-Mental State Examination questionnaire. Logistic regression models, controlled for an extensive range of potential confounders, were generated to …examine the associations between women’s reproductive history and risk of cognitive impairment in their later life. Results: The length of reproductive period was inversely associated with risk of cognitive impairment (p  = 0.001). Odds ratio (OR) of cognitive impairment were 1.316 (95% CI 1.095∼1.582) for women with 5 or more times of full-term pregnancies, compared with those with 1∼4 times of full-term pregnancies. Women without incomplete pregnancy had a significant higher risk of cognitive impairment (OR = 1.194, 95% CI 1.000∼1.429), compared with the reference (1∼2 times of incomplete pregnancies). Oral contraceptive use (OR = 0.489, 95% CI 0.263∼0.910) and intrauterine device (IUD) use (OR = 0.684, 95% CI 0.575∼0.815) were associated with significantly reduced risk of cognitive impairment. Conclusion: Our results indicated that shorter reproductive period, higher number of full-term pregnancies and no incomplete pregnancy history were associated with an increased risk of cognitive impairment. In contrast, oral contraceptive and IUD use corresponded to reduced risk of cognitive impairment. Show more

Keywords: Cognitive impairment, estrogen, intrauterine device, pregnancies, reproductive history

DOI: 10.3233/JAD-150444

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 139-147, 2016

Authors: Mäkelä, Mira | Paetau, Anders | Polvikoski, Tuomo | Myllykangas, Liisa | Tanskanen, Maarit

Article Type: Research Article

Abstract: Background: Capillary amyloid-β (capAβ) deposition in the cerebral cortex is the neuropathological feature providing the basis for categorizing cerebral amyloid angiopathy (CAA) into two distinct types, CAA-Type1 with capAβ and CAA-Type2 without capAβ. Objective: We investigated the neuropathological and clinical characteristics of capAβ deposition in a prospective population-based study. Methods: Vantaa 85+ includes 601 individuals aged ≥85 years, of which 300 were studied clinically and neuropathologically. 278 subjects were analyzed for the apolipoprotein E (APOE) genotype. The diagnosis of capAβ was determined using immunohistochemistry against Aβ, and of CAA using Congo red confirmed by Aβ …immunohistochemistry, both analyzed in six brain areas. The severity of capAβ was graded semi-quantitatively, and the severity of CAA was based on the percentage of affected vessels. Alzheimer’s disease (AD)-type neuropathology (CERAD score and Braak stage) was analyzed using standard methods. Results: CAA-Type1 was present in 86/300, CAA-Type2 in 135/300, and 79/300 had no CAA. CapAβ was most frequent in the occipital lobe (79/86). CAA-Type1 was associated with the severity of CAA (p  <  0.001), dementia (p  <  0.001), severe AD-type neuropathology (p -value 0.09 for CERAD C and 0.017 for Braak stages V-VI), and APOE ɛ 4 allele carrier status (p  <  0.001). Conclusions: This population-based study confirmed the presence of distinct CAA-Type1 and its association with the severity of CAA, severe AD-type neuropathology, and the APOE ɛ 4 carrier status. Both the severity and localization of the deposition seemed to determine the clinical significance of capAβ. Show more

Keywords: Alzheimer’s disease, CAA-Type1, capillary CAA, neuropathology, population-based study

DOI: 10.3233/JAD-150241

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 149-157, 2016

Authors: Lizio, Roberta | Del Percio, Claudio | Marzano, Nicola | Soricelli, Andrea | Yener, Görsev G. | Başar, Erol | Mundi, Ciro | De Rosa, Salvatore | Triggiani, Antonio Ivano | Ferri, Raffaele | Arnaldi, Dario | Nobili, Flavio Mariano | Cordone, Susanna | Lopez, Susanna | Carducci, Filippo | Santi, Giulia | Gesualdo, Loreto | Rossini, Paolo M. | Cavedo, Enrica | Mauri, Margherita | Frisoni, Giovanni B. | Babiloni, Claudio

Article Type: Research Article

Abstract: Here we presented a single electroencephalographic (EEG) marker for a neurophysiological assessment of Alzheimer’s disease (AD) patients already diagnosed by current guidelines. The ability of the EEG marker to classify 127 AD individuals and 121 matched cognitively intact normal elderly (Nold) individuals was tested. Furthermore, its relationship to AD patients’ cognitive status and structural brain integrity was examined. Low-resolution brain electromagnetic tomography (LORETA) freeware estimated cortical sources of resting state eyes-closed EEG rhythms. The EEG marker was defined as the ratio between the activity of parieto-occipital cortical sources of delta (2–4 Hz) and low-frequency alpha (8–10.5 Hz) rhythms. Results showed 77.2% of …sensitivity in the recognition of the AD individuals; 65% of specificity in the recognition of the Nold individuals; and 0.75 of area under the receiver-operating characteristic curve. Compared to the AD subgroup with the EEG maker within one standard deviation of the Nold mean (EEG-), the AD subgroup with EEG+ showed lower global cognitive status, as revealed by Mini-Mental State Evaluation score, and more abnormal values of white-matter and cerebrospinal fluid normalized volumes, as revealed by structural magnetic resonance imaging. We posit that cognitive and functional status being equal, AD patients with EEG+ should receive special clinical attention due to a neurophysiological “frailty”. EEG+ label can be also used in clinical trials (i) to form homogeneous groups of AD patients diagnosed by current guidelines and (ii) as end-point to evaluate intervention effects. Show more

Keywords: Alpha rhythms, Alzheimer’s disease, delta rhythms, electroencephalography, low resolution brain electromagnetic tomography (LORETA), neurophysiological assessment

DOI: 10.3233/JAD-143042

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 159-177, 2016

Authors: Lebwohl, Benjamin | Luchsinger, José A. | Freedberg, Daniel E. | Green, Peter H.R. | Ludvigsson, Jonas F.

Article Type: Research Article

Abstract: Background: Patients with celiac disease (CD) frequently report cognitive symptoms when they are exposed to gluten, and cognitive deficits have been quantified in patients with newly diagnosed CD. Objective: To determine whether patients with CD have an increased risk of dementia. Methods: Using a population-based database of older adults (age ≥50 years) with histologically proven CD (duodenal/jejunal villous atrophy) from all 28 pathology departments in Sweden, we compared the incidence of a subsequent dementia diagnosis to those of age- and gender-matched controls. Results: Among patients with CD (n  = 8,846) and controls (n  = 43,474), the …median age was 63 years and 56% were female. During a median follow-up time of 8.4 years, dementia was diagnosed in 4.3% of CD patients and 4.4% of controls (HR 1.07; 95% CI 0.95–1.20). Although there was an increased risk of dementia in the first year following a diagnosis of CD (HR 1.73; 95% CI 1.15–2.61), this risk was not present in the whole observation period. Among those subjects with a dementia subtype specified, the increased risk was restricted to vascular dementia (HR 1.28; 95% CI 1.00–1.64) and was not present for Alzheimer’s dementia (HR 1.12; 95% CI 0.91–1.37). Conclusions: Patients with CD are not at increased risk for dementia overall, though subgroup analysis suggests that they may be at increased risk for vascular dementia. Show more

Keywords: Alzheimer’s disease, celiac disease, dementia, epidemiology

DOI: 10.3233/JAD-150388

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 179-185, 2016

Authors: García Barrado, Leandro | Coart, Els | Vanderstichele, Hugo M.J. | Burzykowski, Tomasz

Article Type: Research Article

Abstract: Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimer’s disease pathology report different concentrations in function of technology and suffer from between-laboratory variability. Hence, lab- and technology-specific cut-off values are required. It is common practice to establish cut-off values on small datasets and, in the absence of well-characterized samples, to transfer the cut-offs to another assay format using ‘side-by-side’ testing of samples with both assays. We evaluated the uncertainty in cut-off estimation and the performance of two methods of cut-off transfer by using two clinical datasets and simulated data. The cut-off for the new assay was transferred by …applying the commonly-used linear regression approach and a new Bayesian method, which consists of using prior information about the current assay for estimation of the biomarker’s distributions for the new assay. Simulations show that cut-offs established with current sample sizes are insufficiently precise and also show the effect of increasing sample sizes on the cut-offs’ precision. The Bayesian method results in unbiased and less variable cut-offs with substantially narrower 95% confidence intervals compared to the linear-regression transfer. For the BIODEM datasets, the transferred cut-offs for INNO-BIA Aβ1-42 are 167.5 pg/mL (95% credible interval [156.1, 178.0] and 172.8 pg/mL (95% CI [147.6, 179.6]) with Bayesian and linear regression methods, respectively. For the EUROIMMUN assay, the estimated cut-offs are 402.8 pg/mL (95% credible interval [348.0, 473.9]) and 364.4 pg/mL (95% CI [269.7, 426.8]). Sample sizes and statistical methods used to establish and transfer cut-off values have to be carefully considered to guarantee optimal diagnostic performance of biomarkers. Show more

Keywords: Alzheimer’s disease, Bayesian method, biomarker cut-off value, diagnostic accuracy

DOI: 10.3233/JAD-150511

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 187-199, 2016