Journal of Alzheimer's Disease - Volume 54, issue 1

Authors: Jaakkimainen, R. Liisa | Bronskill, Susan E. | Tierney, Mary C. | Herrmann, Nathan | Green, Diane | Young, Jacqueline | Ivers, Noah | Butt, Debra | Widdifield, Jessica | Tu, Karen

Article Type: Research Article

Abstract: Background: Population-based surveillance of Alzheimer’s and related dementias (AD-RD) incidence and prevalence is important for chronic disease management and health system capacity planning. Algorithms based on health administrative data have been successfully developed for many chronic conditions. The increasing use of electronic medical records (EMRs) by family physicians (FPs) provides a novel reference standard by which to evaluate these algorithms as FPs are the first point of contact and providers of ongoing medical care for persons with AD-RD. Objective: We used FP EMR data as the reference standard to evaluate the accuracy of population-based health administrative data …in identifying older adults with AD-RD over time. Methods: This retrospective chart abstraction study used a random sample of EMRs for 3,404 adults over 65 years of age from 83 community-based FPs in Ontario, Canada. AD-RD patients identified in the EMR were used as the reference standard against which algorithms identifying cases of AD-RD in administrative databases were compared. Results: The highest performing algorithm was “one hospitalization code OR (three physician claims codes at least 30 days apart in a two year period) OR a prescription filled for an AD-RD specific medication” with sensitivity 79.3% (confidence interval (CI) 72.9–85.8%), specificity 99.1% (CI 98.8–99.4%), positive predictive value 80.4% (CI 74.0–86.8%), and negative predictive value 99.0% (CI 98.7–99.4%). This resulted in an age- and sex-adjusted incidence of 18.1 per 1,000 persons and adjusted prevalence of 72.0 per 1,000 persons in 2010/11. Conclusion: Algorithms developed from health administrative data are sensitive and specific for identifying older adults with AD-RD. Show more

Keywords: Dementia, electronic medical records, family physician, health administrative algorithm

DOI: 10.3233/JAD-160105

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 337-349, 2016

Authors: Ho, Bo-Lin | Kao, Yi-Hui | Chou, Mei-Chuan | Yang, Yuan-Han

Article Type: Research Article

Abstract: Background : Rivastigmine has been approved in the treatment of Alzheimer’s disease (AD) patients as it can inhibit acetyl- and butyryl-cholinesterase and provide neuroprotective effects involving the synapses. White matter changes (WMCs) are frequently observed in AD, and clinical-pathological correlations imply their possible impacts on cognitive function by interference with cortical and subcortical neuronal pathways. Objective: To evaluate the therapeutic effects of rivastigmine in AD patients with cerebral WMCs. Methods: Clinically diagnosed AD patients from Kaohsiung Municipal Ta-Tung hospital were recruited together with their cranial magnetic resonance imaging and a series of annual psychometric tests, including …Mini-Mental State Examination (MMSE) and sum of boxes of clinical dementia rating scale (CDR-SB). WMCs were rated through the modified Fazekas scale for the periventricular and deep WMCs. Results: In total, 87 AD patients treated with rivastigmine were enrolled. Patients at severe stage of WMCs, compared to mild stage ones, had significant improvement evaluated by MMSE (periventricular WMCs, p  = 0.025; deep WMCs, p  = 0.030), but not CDR-SB. Compared to the worsening group, the clinically improving group had a significant higher ratio of pre-existing hypertension in terms of cognitive performance [p  = 0.016, odds ratio (OR) = 3.48, 95% CI = 1.25–10.34], while having younger age (p  = 0.043, OR = 0.11, 95% CI = 0.01–1.12) in terms of global status. Conclusion: Rivastigmine may provide better benefits in cognitive function, but not global status, for AD patients with more advanced WMCs. The detailed mechanisms still have to be determined in future studies. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, rivastigmine, white matter changes

DOI: 10.3233/JAD-160364

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 351-357, 2016

Authors: Wang, Pingyue | Chen, Kewei | Yao, Li | Hu, Bin | Wu, Xia | Zhang, Jiacai | Ye, Qing | Guo, Xiaojuan | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: In recent years, increasing attention has been given to the identification of the conversion of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Brain neuroimaging techniques have been widely used to support the classification or prediction of MCI. The present study combined magnetic resonance imaging (MRI), 18 F-fluorodeoxyglucose PET (FDG-PET), and 18 F-florbetapir PET (florbetapir-PET) to discriminate MCI converters (MCI-c, individuals with MCI who convert to AD) from MCI non-converters (MCI-nc, individuals with MCI who have not converted to AD in the follow-up period) based on the partial least squares (PLS) method. Two types of PLS models (informed PLS and …agnostic PLS) were built based on 64 MCI-c and 65 MCI-nc from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The results showed that the three-modality informed PLS model achieved better classification accuracy of 81.40%, sensitivity of 79.69%, and specificity of 83.08% compared with the single-modality model, and the three-modality agnostic PLS model also achieved better classification compared with the two-modality model. Moreover, combining the three modalities with clinical test score (ADAS-cog), the agnostic PLS model (independent data: florbetapir-PET; dependent data: FDG-PET and MRI) achieved optimal accuracy of 86.05%, sensitivity of 81.25%, and specificity of 90.77%. In addition, the comparison of PLS, support vector machine (SVM), and random forest (RF) showed greater diagnostic power of PLS. These results suggested that our multimodal PLS model has the potential to discriminate MCI-c from the MCI-nc and may therefore be helpful in the early diagnosis of AD. Show more

Keywords: Classification, mild cognitive impairment, MRI, partial least squares, PET

DOI: 10.3233/JAD-160102

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 359-371, 2016

Authors: Rosenberg, Paul B. | Lanctôt, Krista L. | Herrmann, Nathan | Mintzer, Jacobo E. | Porsteinsson, Anton P. | Sun, Xiaoying | Raman, Rema

Article Type: Research Article

Abstract: Background: In a recent report, 76 weeks’ treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer’s disease (AD). Objective: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). Methods: 1,537 participants with mild to moderate AD were randomized to 76 weeks’ treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer’s Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change …in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline. Results: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased. Conclusion: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD. Show more

Keywords: Alzheimer’s disease, amyloid, clinical trial, depression, neuropsychiatry

DOI: 10.3233/JAD-151113

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 373-381, 2016

Authors: Somers, Charisse | Struyfs, Hanne | Goossens, Joery | Niemantsverdriet, Ellis | Luyckx, Jill | De Roeck, Naomi | De Roeck, Ellen | De Vil, Bart | Cras, Patrick | Martin, Jean-Jacques | De Deyn, Peter-Paul | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimer’s disease (AD) CSF biomarkers: amyloid-β peptide of 42 amino acids (Aβ1-42 ), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P ). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aβ1-42 <638.5 pg/mL, T-tau >296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aβ1-42 concentration was below the cutoff, in combination …with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, dementia, diagnosis, mild cognitive impairment, neuropathology, tau

DOI: 10.3233/JAD-151097

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 383-395, 2016

Authors: Lou, Wutao | Shi, Lin | Wong, Adrian | Chu, Winnie C.W. | Mok, Vincent C.T. | Wang, Defeng

Article Type: Research Article

Abstract: Disruptions of the functional brain network and cerebral blood flow (CBF) have been revealed in patients with mild cognitive impairment (MCI). However, the neurophysiological mechanism of hypoperfusion as well as the reorganization of the intrinsic whole brain network due to the neuropathology of MCI are still unclear. In this study, we aimed to investigate the changes of CBF and the whole brain network organization in MCI by using a multimodal MRI approach. Resting state ASL MRI and BOLD MRI were used to evaluate disruptions of CBF and underlying functional connectivity in 27 patients with MCI and 35 cognitive normal controls …(NC). The eigenvector centrality mapping (ECM) was used to assess the whole brain network reorganization in MCI, and a seed-based ECM approach was proposed to reveal the contributions of the whole brain network on the ECM alterations. Significantly decreased perfusion in the posterior parietal cortex as well as its connectivity within the default mode network and occipital cortex were found in the MCI group compared to the NC group. The ECM analysis revealed decreased EC in the middle cingulate cortex, parahippocampal gyrus, medial frontal gyrus, and increased EC in the right calcarine sulcus, superior temporal gyrus, and supplementary motor area in the MCI group. The results of this study indicate that there are deficits in cerebral blood flow and functional connectivity in the default mode network, and that sensory-processing networks might play a compensatory role to make up for the decreased connections in MCI. Show more

Keywords: Cerebral blood flow, eigenvector centrality, functional connectivity, functional MRI, mild cognitive impairment

DOI: 10.3233/JAD-160201

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 397-409, 2016

Article Type: Other

DOI: 10.3233/JAD-160670

Citation: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 411-415, 2016