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

Authors: Idland, Ane-Victoria | Wyller, Torgeir Bruun | Støen, Randi | Eri, Lars Magne | Frihagen, Frede | Ræder, Johan | Chaudhry, Farrukh Abbas | Hansson, Oskar | Zetterberg, Henrik | Blennow, Kaj | Bogdanovic, Nenad | Brækhus, Anne | Watne, Leiv Otto

Article Type: Research Article

Abstract: Background: The clinical relevance of brain β-amyloidosis in older adults without dementia is not established. As delirium and dementia are strongly related, studies on patients with delirium may give pathophysiological clues. Objective: To determine whether the Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42 ), total tau (T-tau), and phosphorylated tau (P-tau) are associated with delirium in hip fracture patients with and without dementia. Methods: CSF was collected in conjunction to spinal anesthesia in 129 patients. Delirium was assessed using the Confusion Assessment Method once daily in all patients, both pre- and postoperatively. …The diagnosis of dementia at admission was based upon clinical consensus. CSF levels of Aβ42 , T-tau, and P-tau were analyzed. Results: In patients without dementia, we found lower CSF Aβ42 levels (median, 310 ng/L versus 489 ng/L, p  = 0.006), higher T-tau levels (median, 505 ng/L versus 351 ng/L, p  = 0.02), but no change in P-tau in patients who developed delirium (n  = 16) compared to those who remained lucid (n  = 49). Delirious patients also had lower ratios of Aβ42 to T-tau (p  < 0.001) and P-tau (p  = 0.001) relative to those without delirium. CSF Aβ42 and T-tau remained significantly associated with delirium status in adjusted analyses. In patients with dementia, CSF biomarker levels did not differ between those with (n  = 54) and without delirium (n  = 10). Conclusion: The reduction in CSF Aβ42 , indicating β-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, delirium, dementia, physiopathology

DOI: 10.3233/JAD-160461

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 371-379, 2017

Authors: Kim, Julia | Schweizer, Tom A. | Fischer, Corinne E. | Munoz, David G.

Article Type: Research Article

Abstract: Background: The pathophysiology behind psychosis in patients with Alzheimer’s disease (AD) remains unknown. Recently, vascular risk factors have been recognized as important modifiers of the clinical presentation of AD. Objective: The purpose of our study is to investigate the mechanism through which vascular risk factors mediate psychosis and whether or not it involves cerebrovascular lesions. Methods: Data was provided by the National Alzheimer’s Coordinating Centre. The Uniform Data Set was used to collect information on subject-reported history of vascular risk factors, clinician-reported state of cognitive performance, and presence of psychosis based on the Neuropsychiatric Inventory …Questionnaire (NPI-Q). The Neuropathology Data Set was used to evaluate the presence of vascular lesions and the severity of AD pathology. Subjects with high probability of AD based on the NIA/AA Reagan criteria were included in the analysis. Results: We identified 1,459 patients with high probability of AD and corresponding NPI-Q scores. We confirmed the association between hypertension and diabetes on psychosis, specifically in delusions and the co-occurrence of delusions and hallucinations. Furthermore, the presence of white matter rarefaction based on pathological evaluation was associated with hallucinations. A history of vascular risk factors was positively associated with vascular lesions. However, vascular lesions in the presence of vascular risk factors did not increase the likelihood of psychosis. Furthermore, vascular lesions were not associated with greater cognitive or functional impairments in this group with severe AD pathology. Conclusion: Vascular risk factors and vascular lesions are independently associated with psychosis in patients with severe AD. However, vascular lesions are not the mechanism through which vascular risk factors mediate psychosis. Show more

Keywords: Cerebrovascular diseases, delusions, dementia, hallucinations, infarction, neuropathology, pathology, risk factors, vascular

DOI: 10.3233/JAD-160506

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 381-389, 2017

Authors: Fisher, Carolyn L. | Resnick, Ross J. | De, Soumya | Acevedo, Lucila A. | Lu, Kun Ping | Schroeder, Frank C. | Nicholson, Linda K.

Article Type: Research Article

Abstract: The cis /trans isomerization of X-Pro peptide bonds in proteins in some instances acts as a molecular switch in biological pathways. Our prior work suggests that the cis isomer of the phospho-Thr668-Pro669 motif, located in the cytoplasmic domain of the amyloid-β protein precursor (AβPP), is correlated with an increase in amyloidogenic processing of AβPP and production of amyloid-beta (Aβ), the neurotoxic peptide fragment in Alzheimer’s disease (AD). We designed a 100% cis -locked cyclic dipeptide composed of cyclized phospho-Thr-Pro (pCDP) as a mimic for this putative pathological conformation, and three phosphate-blocked derivatives (pCDP-diBzl, pCDP-Bzl, and pCDP-diPOM). Two H4 …neuroglioma cell lines were established as AD cell models for use in testing these compounds: H4-AβPP695 for stable overexpression of wild-type AβPP695, and H4-BACE1 for stable overexpression of β-site AβPP cleaving enzyme-1 (BACE1). The level of the secreted AβPP fragment resulting from BACE1 activity, sAβPPβ, served as a key proxy for amyloidogenic processing, since cleavage of AβPP by BACE1 is a requisite first step in Aβ production. Of the compounds tested, pCDP-diBzl decreased sAβPPβ levels in both cell lines, while pCDP-diPOM decreased sAβPPβ levels in only H4-BACE1 cells, all with similar dose-dependences and patterns of proteolytic AβPP fragments. Enzymatic assays showed that none of the pCDP derivatives directly inhibit BACE1 catalytic activity. These results suggest a model in which pCDP-diBzl and pCDP-diPOM act at a common point to inhibit entry of AβPP into the amyloidogenic AβPP processing pathway but through different targets, and provide important insights for the development of novel AD therapeutics. Show more

Keywords: Alzheimer’s disease, amyloid beta-protein precursor, cyclic dipeptides, diketopiperazine, phosphorylated Thr668

DOI: 10.3233/JAD-160051

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 391-410, 2017

Authors: Banks, William A. | Kovac, Andrej | Majerova, Petra | Bullock, Kristin M. | Shi, Min | Zhang, Jing

Article Type: Research Article

Abstract: Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer’s disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151–391 (0N4R), and truncated tau 121–227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau …proteins also entered the blood after their injection into the brain, with Tau 121–227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, tau protein, tauopathy

DOI: 10.3233/JAD-160542

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 411-419, 2017

Authors: Serra, Laura | Mancini, Matteo | Cercignani, Mara | Di Domenico, Carlotta | Spanò, Barbara | Giulietti, Giovanni | Koch, Giacomo | Marra, Camillo | Bozzali, Marco

Article Type: Research Article

Abstract: Cognitive reserve (CR) is known to modulate the clinical features of Alzheimer’s disease (AD). This concept may be critical for the development of non-pharmacological interventions able to slow down patients’ cognitive decline in the absence of disease-modifying treatments. We aimed at identifying the neurobiological substrates of CR (i.e., neural reserve) over the transition between normal aging and AD, by assessing the underlying brain networks and their topological properties. A cohort of 154 participants (n  = 68 with AD, n  = 61 with amnestic mild cognitive impairment (aMCI), and 25 healthy subjects) underwent resting-state functional MRI and neuropsychological testing. Within each group, participants …were classified as having high or low CR, and functional connectivity measures were compared, within group, between high and low CR individuals. Network-based statistics and topological network properties derived from graph theory were explored. Connectivity differences between high and low CR were evident only for aMCI patients, with participants with high CR showing a significant increase of connectivity in a network involving mainly fronto-parietal nodes. Conversely, they showed significantly decreased connectivity in a network involving fronto-temporo-cerebellar nodes. Consistently, changes to topological measures were observed in either direction, and were associated with measures of global cognitive function. These findings support the hypothesis that CR impacts on neurodegenerative process in the early phase of AD only. In addition, they fit with the existence of a “neural reserve”, characterized by specific neural networks and their efficiency. It remains to be demonstrated whether interventions later in life can modulate this “neural reserve”. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, brain connectivity, cognitive reserve, compensatory network, neural reserve

DOI: 10.3233/JAD-160735

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 421-430, 2017

Authors: Grau-Rivera, Oriol | Calvo, Anna | Bargalló, Núria | Monté, Gemma C. | Nos, Carlos | Lladó, Albert | Molinuevo, José Luis | Gelpi, Ellen | Sánchez-Valle, Raquel

Article Type: Research Article

Abstract: Background: Quantitative neuroimaging might unveil abnormalities in prion diseases that are not perceivable at visual inspection. On the other hand, scarce studies have quantified volumetric changes in prion diseases. Objectives: We aim to characterize volumetric and diffusion tensor imaging (DTI) changes in patients with prion diseases who presented with either Creutzfeldt-Jakob disease (CJD) or fatal insomnia (FI) phenotype. Methods: Twenty patients with prion diseases— 15 with CJD and 5 with fatal insomnia (FI)— and 40 healthy controls were examined with a 3-Tesla magnetic resonance imaging scanner. Images were segmented and normalized with SPM12. DTI maps …were obtained with FMRIB Software Library. Whole-brain voxel-wise and region-of-interest analyses of volumetric and DTI changes were performed with SPM12. White matter (WM) changes were also analyzed with tract-based spatial statistics. Semiquantitive assessment of neuropathological parameters was compared with DTI metrics in thalamus from 11 patients. Results: Patients with CJD and FI presented significant atrophy in thalamus and cerebellum. In CJD, mean diffusivity (MD) was decreased in striatum and increased in subcortical WM, while both increased and decreased values were observed across different thalamic nuclei. In FI, MD was increased in thalamus and cerebellum. Spongiform change and PrPSc deposition were more intense in thalamus in CJD than in FI, although no significant correlations arose with MD values in the nuclei studied. Conclusion: Volumetric and DTI abnormalities suggest a central common role of the thalamus in prion diseases. We report, for the first time, quantitative MRI changes in FI, and provide further evidence of WM involvement in prion diseases. Show more

Keywords: Creutzfeldt-Jakob syndrome, diffusion tensor imaging, fatal familial insomnia, neuroimaging, prion diseases

DOI: 10.3233/JAD-160750

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 431-443, 2017

Article Type: Retraction

DOI: 10.3233/JAD-179001

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 445-445, 2017