Journal of Alzheimer's Disease - Volume 55, issue 1

Authors: Jacob, Louis | Han, Ji Won | Kim, Tae Hui | Park, Joon Hyuk | Lee, Seok Bum | Lee, Jung Jae | Ryu, Seung-Ho | Kim, Shin-Kyeom | Yoon, Jong Chul | Jhoo, Jin Hyeong | Kim, Jeong Lan | Kwak, Kyung Phil | Moon, Seok Woo | Kim, Bong Jo | Lee, Dong Young | Kim, Ki Woong

Article Type: Research Article

Abstract: Background: Measurements of patient quality of life (QoL) play a major role in the management of dementia. Objective: We investigated the self-proxy discrepancy of QoL ratings in the elderly and the impact of dementia severity on the discrepancy. Methods: QoL of 718 patients with dementia and 651 non-demented elderly were rated by themselves and their caregivers (CG) using the Quality of Life-Alzheimer’s Disease (QoL-AD). The impact of the rater on the total and item scores of QoL-AD was analyzed using repeated measures ANOVA and differential response patterns between self and proxy were analyzed using differential …item functioning (DIF) analysis. Results: Self-rated scores were higher than CG-rated scores in all diagnostic groups. The interaction between rater and diagnostic group was significant in total QoL-AD score and 5 item scores (‘memory’, ‘marriage’, ‘chores around the house’, ‘do things for fun’, and ‘life as a whole’). The strength of the DIF increased with advancing dementia in these items. Conclusion: Self-proxy rating discrepancy of QoL was influenced by the presence and severity of dementia only in five items. Show more

Keywords: Caregiver, dementia, discrepancy, proxy, quality of life, self

DOI: 10.3233/JAD-160538

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 259-267, 2017

Authors: Ardekani, Babak A. | Bermudez, Elaine | Mubeen, Asim M. | Bachman, Alvin H. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a transitional stage from normal aging to Alzheimer’s disease (AD) dementia. It is extremely important to develop criteria that can be used to separate the MCI subjects at imminent risk of conversion to Alzheimer-type dementia from those who would remain stable. We have developed an automatic algorithm for computing a novel measure of hippocampal volumetric integrity (HVI) from structural MRI scans that may be useful for this purpose. Objective: To determine the utility of HVI in classification between stable and progressive MCI patients using the Random Forest classification algorithm. Methods: …We used a 16-dimensional feature space including bilateral HVI obtained from baseline and one-year follow-up structural MRI, cognitive tests, and genetic and demographic information to train a Random Forest classifier in a sample of 164 MCI subjects categorized into two groups [progressive (n  = 86) or stable (n  = 78)] based on future conversion (or lack thereof) of their diagnosis to probable AD. Results: The overall accuracy of classification was estimated to be 82.3% (86.0% sensitivity, 78.2% specificity). The accuracy in women (89.1%) was considerably higher than that in men (78.9%). The prediction accuracy achieved in women is the highest reported in any previous application of machine learning to AD diagnosis in MCI. Conclusion: The method presented in this paper can be used to separate stable MCI patients from those who are at early stages of AD dementia with high accuracy. There may be stronger indicators of imminent AD dementia in women with MCI as compared to men. Show more

Keywords: Alzheimer’s disease, atrophy, hippocampus, longitudinal analysis, magnetic resonance imaging, mild cognitive impairment, prediction, Random Forest, sex

DOI: 10.3233/JAD-160594

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 269-281, 2017

Authors: Myung, Woojae | Lee, Chunsoo | Park, Jin Hong | Woo, Sook-young | Kim, Seonwoo | Kim, Sangha | Chung, Jae Won | Kang, Hyo Shin | Lim, Shinn-Won | Choi, Junbae | Na, Duk L. | Kim, Seong Yoon | Lee, Jae-Hong | Han, Seol-Heui | Choi, Seong Hye | Kim, Sang Yun | Carroll, Bernard J. | Kim, Doh Kwan

Article Type: Research Article

Abstract: High occupational attainment has been known as a marker of cognitive reserve. Previous studies in the general population have shown that high occupational attainment is associated with reduced risk of Alzheimer’s disease (AD). However, few studies have assessed the effect of occupational attainment on the clinical course of mild cognitive impairment (MCI). In this study, we evaluated whether individuals with high occupational attainment show more frequent progression from MCI to AD. Participants (n  = 961) with MCI were recruited from a nationwide, hospital-based multi-center cohort, and were followed for up to 60 months (median: 17.64, interquartile range [12.36, 29.28 ]). We …used Cox regression for competing risks to analyze the effect of occupational attainment on development of AD, treating dementia other than AD as a competing risk. Among the 961 individuals with MCI, a total of 280 (29.1%) converted to dementia during the follow-up period. The risk of progression to AD was higher in the individuals with high occupational attainment after controlling for potential confounders (hazard ratio = 1.83, 95% confidence interval = 1.25–2.69, p  = 0.002). High occupational attainment in individuals with MCI is an independent risk factor for higher progression rate of MCI to AD. This result suggests that the protective effect of high occupational attainment against cognitive decline disappears in the MCI stage, and that careful assessment of occupational history can yield important clinical information for prognosis in individuals with MCI. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, occupational attainment, progression

DOI: 10.3233/JAD-160257

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 283-292, 2017

Authors: Shim, Sung-Mi | Cheon, Hyo-Soon | Jo, Chulman | Koh, Young Ho | Song, Jihyun | Jeon, Jae-Pil

Article Type: Research Article

Abstract: Chronic viral infection is implicated in cognitive decline and Alzheimer’s disease (AD). Our goal was to identify biomarkers for the development of amnestic mild cognitive impairment (aMCI) from cognitively normal state. To accomplish this, we analyzed plasma IgG levels against Epstein-Barr virus (EBV) and herpes simplex virus 1 (HSV-1) in study subjects with incident aMCI (Converter) and normal cognitive function (NC Control) who did or did not convert from cognitively normal state to aMCI during the 2-year follow-up period, respectively. The Converter group exhibited elevated levels of anti-EBV IgG antibodies in the post-follow-up phase (aMCI state) compared to the pre-follow-up …phase (cognitively normal state), but not the NC Control group. In contrast, the total IgG level was not significantly changed over the follow-up period. Moreover, elevated anti-EBV IgG levels were significantly associated with CDR scales and total CERAD scores in the Converter group. These results suggest that EBV infection or its related host immune response is linked to cognitive decline. Thus, an EBV antibody level may be used as a potential biomarker for assessing the risk of aMCI development, implying a role for chronic EBV infection in AD pathogenesis. Show more

Keywords: Amnestic mild cognitive impairment, biomarker, cognitive decline, EBV antibody

DOI: 10.3233/JAD-160563

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 293-301, 2017

Authors: Russell, Claire L. | Mitra, Vikram | Hansson, Karl | Blennow, Kaj | Gobom, Johan | Zetterberg, Henrik | Hiltunen, Mikko | Ward, Malcolm | Pike, Ian

Article Type: Research Article

Abstract: Aberrant tau phosphorylation is a hallmark in Alzheimer’s disease (AD), believed to promote formation of paired helical filaments, the main constituent of neurofibrillary tangles in the brain. While cerebrospinal fluid (CSF) levels of total tau and tau phosphorylated at threonine residue 181 (pThr181) are established core biomarkers for AD, the value of alternative phosphorylation sites, which may have more direct relevance to pathology, for early diagnosis is not yet known, largely due to their low levels in CSF and lack of standardized detection methods. To overcome sensitivity limitations for analysis of phosphorylated tau in CSF, we have applied an innovative …mass spectrometry (MS) workflow, TMTcalibratortrademark, to enrich and enhance the detection of phosphoproteome components of AD brain tissue in CSF, and enable the quantitation of these analytes. We aimed to identify which tau species present in the AD brain are also detectable in CSF and which, if any, are differentially regulated with disease. Over 75% coverage of full-length (2N4R) tau was detected in the CSF with 47 phosphopeptides covering 31 different phosphorylation sites. Of these, 11 phosphopeptides were upregulated by at least 40%, along with an overall increase in tau levels in the CSF of AD patients relative to controls. Use of the TMTcalibratortrademark workflow dramatically improved our ability to detect tau-derived peptides that are directly related to human AD pathology. Further validation of regulated tau peptides as early biomarkers of AD is warranted and is currently being undertaken. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, mass spectrometry, neurodegenerative disease, phosphorylation, post translational modifications, tau

DOI: 10.3233/JAD-160633

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 303-313, 2017

Authors: Zimetti, Francesca | Caffarra, Paolo | Ronda, Nicoletta | Favari, Elda | Adorni, Maria Pia | Zanotti, Ilaria | Bernini, Franco | Barocco, Federica | Spallazzi, Marco | Galimberti, Daniela | Ricci, Chiara | Ruscica, Massimiliano | Corsini, Alberto | Ferri, Nicola

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other apoE-binding receptors involved in neuron cholesterol uptake. The role of PCSK9 in AD is controversial. Objective: We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with CSF total apoE and apoE4. Methods: CSF from AD (n  = 30) and from age and sex-matched …non-AD patients (n  = 30) was collected by lumbar puncture for routine diagnosis. CSF PCSK9, total apoE, and apoE4 levels were measured by ELISA. AD patients showed the typical CSF neurobiomarker pattern (decreased Aβ42 and increased tau and phospho-tau) and impaired cognitive performances, as indicated by the scores of the Mini-Mental State Examination test. Results: PCSK9 levels in CSF were higher in AD than in non-AD subjects (+1.45 fold; p  = 0.0049). CSF total apoE concentrations did not differ between the two groups, while apoE4 levels were higher in AD subjects (+3.34 fold; p  = 0.0068). Considering all samples, a significant positive correlation was found between PCSK9 and apoE4 (r = 0.4409; p  = 0.0006). PCSK9 levels were higher in APOE ɛ 4 carriers, reaching statistical significance in the AD group (+1.45 fold; p  = 0.0454). Conclusion: These results report for the first time an alteration of CSF PCSK9 levels in AD and suggest a pathophysiological link between PCSK9, apoE4, and AD. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, cerebrospinal fluid, cholesterol, human, proprotein convertase subtilisin kexin 9

DOI: 10.3233/JAD-160411

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 315-320, 2017

Authors: Leger, Damien | Elbaz, Maxime | Dubois, Alexandre | Rio, Stéphane | Mezghiche, Hocine | Carita, Paulo | Stemmelin, Jeanne | Strauss, Melanie

Article Type: Research Article

Abstract: Background: In epidemiological surveys, cognitive decline has been found to be associated with both short and long sleep duration. Objective: Our goal was to objectively determine how total sleep time (TST) at night was associated or not with apathy or severity scores in patients with Alzheimer ’s disease (AD). Methods: During an observational first step of a clinical trial, sleep was assessed in institutionalized patients with mild or moderate AD using actigraphy (MW8, Camtech, Cambridge, UK) for 14 consecutive 24-hour periods. Sleep parameters analyzed were: TST, time in bed (TIB), wake after sleep onset (WASO), …sleep efficiency (SE) defined by the ratio TST/TIB, in percentage), the number and length of awakenings, the night fragmentation index, the interdaily stability, and intradaily variability indexes. Statistical association analyses were tested between these values and AD apathy and severity scores. Results: 208 individuals coming from 82 centers worldwide (France, Germany, Spain, Italy, Portugal, Poland, United States, Canada, and Australia) and≥50 years old participated. Their average TST was 7 hours and 35 minutes and the average WASO 58 minutes. TST and SE were significantly higher in patients with apathy and the number of awakenings was significantly lower. TST was also positively associated with functional disability (ADCS-ADL scores), but it was not found significantly greater in patients with a moderate AD severity compared to the mild. Conclusion: Despite several and long awakenings, TST was not shorter in patients with AD. TST was even significantly increased with disability and apathy. Show more

Keywords: Actigraphy, Alzheimer’s disease, apathy, severity, sleep, total sleep time

DOI: 10.3233/JAD-160754

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 321-331, 2017

Authors: Freeze, Whitney M. | Jacobs, Heidi I. L. | Gronenschild, Ed H. | Jansen, Jacobus F. A. | Burgmans, Saartje | Aalten, Pauline | Clerx, Lies | Vos, Stephanie J. | van Buchem, Mark A. | Barkhof, Frederik | van der Flier, Wiesje M. | Verbeek, Marcel M. | Rikkert, Marcel Olde | Backes, Walter H. | Verhey, Frans R. | on behalf of the LeARN project

Article Type: Research Article

Abstract: Cerebral small vessel disease (cSVD) and amyloid-β (Aβ) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aβ have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer’s disease (AD) (n  = 24), mild cognitive impairment (MCI) (n  = 26), and subjective cognitive complaints (SCC) (n  = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aβ pathology was assessed as cerebrospinal fluid-derived Aβ1 - 42 levels and dichotomized into …normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aβ on HV in the total participant group (n  = 87) and in the non-demented group (including SCC and MCI individuals only, n  = 63). The results revealed that abnormal Aβ and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aβ and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aβ42 levels, but not in individuals with normal CSF Aβ42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aβ levels are at an increased risk of accelerated disease progression when concomitant cSVD is present. Show more

Keywords: Amyloid-beta, cerebral small vessel disease, dementia, neurodegeneration

DOI: 10.3233/JAD-160474

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 333-342, 2017

Authors: Araque Caballero, Miguel Ángel | Klöppel, Stefan | Dichgans, Martin | Ewers, Michael | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: A substantial proportion of cognitively healthy elders (HC) show abnormally high amyloid-β (Aβ) deposition, a major pathology of Alzheimer’s disease (AD). These subjects are at increased risk of Alzheimer’s disease (AD) dementia, and biomarkers are needed to predict their cognitive deterioration. Here we used relevance vector regression (RVR), a pattern-recognition method, to predict concurrent cognitive decline on the basis of longitudinal gray matter (GM) changes, within two a priori , meta-analytically defined functional networks subserving episodic memory and executive function. Ninety-six HC subjects were assessed annually for three years with structural MRI and cognitive tests within the Alzheimer’s Disease Neuroimaging Initiative. Presence …of abnormal biomarker values of Aβ (Aβ+) were determined with cerebrospinal fluid and amyloid-PET (HC-Aβ+, n =30; with n =66 for normal HC-Aβ–). Using leave-one-out cross-validation, we found that in HC-Aβ+ patterns of GM changes within both networks predicted decline in episodic memory (r=0.61, p <0.001; r=0.40, p =0.03), but not executive function. In HC-Aβ–, GM changes within the executive function network predicted decline in executive function (r =0.44, p <0.001). Previously established region-of-interest (ROI)-based predictors such as changes in hippocampal volume, within an AD-signature multi-ROI, or total GM volume were not predictive of cognitive decline in any group or cognitive domain. RVR analyses unrestricted to the a priori networks yielded compatible results with the restricted case. In conclusion, RVR-derived patterns of subtle cortical GM changes are biomarker candidates of concurrent cognitive decline in aging and subjects at risk for AD. Show more

Keywords: Aging, Alzheimer’s disease, atrophy, gray matter, longitudinal, magnetic resonance imaging, multivariate, pattern recognition, relevance vector regression

DOI: 10.3233/JAD-160327

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 343-358, 2017

Authors: Kara, Kaffer | Mahabadi, Amir Abbas | Weimar, Christian | Winkler, Angela | Neumann, Till | Kälsch, Hagen | Dragano, Nico | Moebus, Susanne | Erbel, Raimund | Jöckel, Karl-Heinz | Jokisch, Martha

Article Type: Research Article

Abstract: Background: N-terminal pro-B type natriuretic peptide (NT-proBNP) is a marker of cardiac stress and is linked with silent cardiac diseases. While associations of cognitive impairment with manifest cardiovascular diseases are established, data on whether subclinical elevation of NT-proBNP levels below clinically established threshold of heart failure is related with cognitive functioning, especially mild cognitive impairment (MCI), is rare. Objective: Aim of the present study was to investigate the cross-sectional association of NT-proBNP levels and MCI in a population-based study sample without heart failure. Methods: We used data from the second examination of the population based …Heinz-Nixdorf-Recall-Study. Subjects with overt coronary heart disease and subjects with NT-proBNP levels indicating potential heart failure (NT-proBNP≥300 pg/ml) were excluded from this analysis. Participants performed a validated brief cognitive assessment and were classified either as MCI [subtypes: amnestic-MCI (aMCI), non-amnestic-MCI (naMCI)], or cognitively-normal. Results: We included 419 participants with MCI (63.1±7.4 y; 47% men; aMCI n  = 209; naMCI n  = 210) and 1,206 cognitively normal participants (62.42±7.1 y; 48% men). NT-proBNP-levels≥125 pg/ml compared to <125 pg/ml were associated with MCI in fully adjusted models (OR 1.65 (1.23;2.23) in the total sample, 1.73 (1.09;2.74) in men and 1.63(1.10;2.41) in women). For aMCI, the fully adjusted OR was 1.53 (1.04;2.25) and for naMCI, the fully adjusted OR was 1.34 (1.09; 166) in the total sample. Conclusion: Within normal ranges and without manifest heart failure, higher NT-proBNPlevels are associated with MCI and both MCI subtypes independent of traditional cardiovascular risk factors and sociodemographic parameters. Show more

Keywords: Alzheimer’s disease, BNP, mild cognitive impairment, natriuretic peptides, NT-proBNP

DOI: 10.3233/JAD-160635

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 359-369, 2017