Journal of Alzheimer's Disease - Volume 62, issue 4

Authors: Kalheim, Lisa Flem | Fladby, Tormod | Coello, Christopher | Bjørnerud, Atle | Selnes, Per

Article Type: Research Article

Abstract: Flutemetamol (18 F-Flut) is an [18 F]-labelled amyloid PET tracer with increasing availability. The main objectives of this study were to investigate 1) cerebrospinal fluid (CSF) Aβ 1-42 (Aβ42 ) concentrations associated with regional 18 F-Flut uptake, 2) associations between cortical 18 F-Flut and [18 F]-fludeoxyglucose (18 F-FDG)-PET, and 3) the potential use of 18 F-Flut in WM pathology. Cognitively impaired, nondemented subjects were recruited (n  = 44). CSF was drawn, and 18 F-Flut-PET, 18 F-FDG-PET, and MRI performed. Our main findings were: 1) Different Alzheimer’s disease predilection areas showed increased 18 F-Flut retention at different CSF Aβ42 concentrations (posterior …regions were involved at higher concentrations). 2) There were strong negative correlations between regional cortical 18 F-Flut and 18 F-FDG uptake. 3) Increased 18 F-Flut uptake were observed in multiple subcortical regions in amyloid positive subjects, including investigated reference regions. However, WM hyperintensity 18 F-Flut standardized uptake value ratios (SUVr) were not significantly different, thus we cannot definitely conclude that the higher uptake in 18 F-Flut(+) is due to amyloid deposition. In conclusion, our findings support clinical use of CSF Aβ42 , putatively relate decreasing CSF Aβ42 concentrations to a sequence of regional amyloid deposition, and associate amyloid pathology to cortical hypometabolism. However, we cannot conclude that 18 F-Flut-PET is a suitable marker for WM pathology due to high aberrant WM uptake. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, imaging, positron emission tomography, white matter disease

DOI: 10.3233/JAD-170582

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1595-1607, 2018

Authors: Yang, Heyun | Hou, Tingting | Wang, Wei | Luo, Yumin | Yan, Feng | Jia, Jianping

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and cerebrovascular disease often coexist. However, it is difficult to determine how chronic cerebral hypoperfusion affects the metabolism of amyloid-β peptides (Aβ) in a living patient with AD. Thus, we developed an animal model of this condition, using transgenic mice (PS1V97L) and right common carotid artery ligation to create chronic cerebral hypoperfusion. The metabolic processes associated with amyloid-β peptide (Aβ) were observed and evaluated in this PS1V97L plus hypoperfusion model. Compared with control mice, the model revealed significantly upregulated expression of Aβ (including Aβ oligomers), with decreased α-secretase activity and expression and increased β-secretase activity and expression. …Furthermore, the model revealed increased mRNA and protein expression of the receptor for advanced glycation end products (RAGE) and decreased mRNA and protein expression of low-density lipoprotein receptor-related protein 1 (LRP-1); both these are Aβ transporters. Moreover, the model revealed decreased activity and expression of neprilysin, which is a peripheral Aβ degrading enzyme. These findings suggest that hypoperfusion may magnify the effect of AD on Aβ metabolism by aggravating its abnormal production, transport, and clearance. Show more

Keywords: Alzheimer’s disease, amyloid-β, chronic cerebral hypoperfusion, metabolism, oligomers, transgenic mice

DOI: 10.3233/JAD-171094

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1609-1621, 2018

Authors: Gallucci, Maurizio | Piovesan, Cinzia | Di Battista, Maria Elena

Article Type: Research Article

Abstract: Background: Frailty is a condition which is characterized by a reduction in the homeostatic reserves of the individual and which entails an increased vulnerability to stressful endogenous and exogenous agents. The Frailty Index (FI), proposed by Rockwood, was designed following an accumulation of deficits model: the greater the number of deficits in a given individual, the greater the degree of frailty. Objective: The aim of this study was to verify the existence of associations between FI and cerebral atrophy. Methods: The TREDEM Register (Treviso Dementia) provided retrospective observational data from 1,584 patients. The FI was calculated …based on 50 variables comprising diseases, disability, behavioral disturbances, and blood chemistry parameters. The severity of atrophy in the cortical and subcortical regions, such as the amplitude of the lateral ventricles, were detected by computerized axial tomography (CAT). Multiple logistic regression models using the stepwise backward method were used to analyze possible associations between FI and atrophy. Results: For each increment of one hundredth of the FI, the probability of cortical atrophy increases by 2%. The female gender is a protective factor for cortical and subcortical atrophy. At each increase of one percent of the FI, the probability of a severe degree of cortical atrophy increases by 3%. The FI was significantly associated with frontal and temporal cortical atrophy. The relationship between overall subcortical atrophy and the FI was not significant, whereas it was the one with the severe degree of subcortical atrophy. The FI is significantly associated with the atrophy of the peri-insular subcortical region. Similar associations were found considering only demented patients. Conclusion: The FI is associated with the presence, degree, and some localization of cerebral atrophy in a population of cognitive-decline patients. Show more

Keywords: Alzheimer’s disease, brain atrophy, dementia, Frailty Index, TREDEM

DOI: 10.3233/JAD-170938

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1623-1634, 2018

Authors: Mehta, Pankaj D. | Patrick, Bruce A. | Barshatzky, Marc | Mehta, Sangita P. | Frackowiak, Janusz | Mazur-Kolecka, Bozena | Wegiel, Jerzy | Wisniewski, Thomas | Miller, David L.

Article Type: Research Article

Abstract: N-terminally truncated pyroglutamate amyloid-β (Aβ) peptide starting at position 3 represents a significant fraction of Aβ peptides (pE3 -Aβ) in amyloid plaques of postmortem brains from patients with Alzheimer’s disease (AD) and older persons with Down syndrome (DS). Studies in transgenic mouse models of AD also showed that pE3 -Aβ is a major component of plaques, and mouse monoclonal antibody to pE3 -Aβ appears to be a desirable therapeutic agent for AD. Since small peptides do not typically elicit a good immune response in mice, but do so favorably in rabbits, our aims were to generate and partially characterize a …rabbit monoclonal antibody (RabmAb) to pE3 -Aβ. The generated RabmAb was found to be specific for pE3 -Aβ, since it showed no reactivity with Aβ16 , Aβ40 , Aβ42 , Aβ3-11 , and pE11-17 Aβ peptides in an enzyme linked immunosorbent assay (ELISA). The isotype of the antibody was found to be IgG class. The antibody possesses high affinity to pE3 -Aβ with dissociation constant (KD ) for the antibody of 1 nM. The epitope of the antibody lies within the sequence of pE3 -FRHD. In dot blotting, the optimal detection of pE3 -Aβ was at an antibody concentration of 0.5 μg/ml. The threshold of pE3 -Aβ detection was 2 fmol. The antibody was sensitive enough to detect 10 pg/ml of pE3 -Aβ in sandwich ELISA. pE3 -Aβ was detected in AD and DS brain extracts in ELISA and immunoblotting. Immunohistological studies showed immunolabeling of plaques and blood vessels in brains from patients with AD, and DS showing AD pathology. Thus, the antibody can be widely applied in AD and DS research, and therapeutic applications. Show more

Keywords: Alzheimer’s disease, Down syndrome, ELISA, partial characterization, pyroglutamate-3 amyloid-β (Aβ) peptide (pE3-Aβ), rabbit monoclonal antibody to pE3-Aβ

DOI: 10.3233/JAD-170898

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1635-1649, 2018

Authors: Yuki-Nozaki, Sohshi | Noguchi-Shinohara, Moeko | Domoto, Chiaki | Ikeda, Yoshihisa | Samuraki, Miharu | Iwasa, Kazuo | Yokogawa, Masami | Asai, Kimiko | Komai, Kiyonobu | Nakamura, Hiroyuki | Yamada, Masahito

Article Type: Research Article

Abstract: In many cohort studies of dementia, while differences in sociodemographic characters between responders and non-responders of dementia screening have been reported, differences in dementia beliefs have been relatively less known. The aims of this study were to clarify dementia beliefs and to explore potential impacts on an intention to attend a future dementia screening in public screeners and in-home screeners, respectively. We performed a cross-sectional population-based study using a question about an intention to attend a future dementia screening and a questionnaire on dementia beliefs. Subjects were all residents aged 65 years or older in the north area of Nakajima, …Japan (n  = 385). All subjects were asked to attend a public dementia screening first. An in-home dementia screening was subsequently conducted in subjects with non-responders to a public screening. The questionnaire consisted of four dementia beliefs: “perceived susceptibility,” “perceived severity,” “perceived barriers,” and “perceived benefits.” Public screeners significantly expressed an intention to attend a future dementia screening more than in-home screeners (p  = 0.002). In in-home screeners, low “perceived severity” were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 0.51 (0.32–0.80)]. In both public and in-home screeners, high “perceived benefits” were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 2.13 (1.46–3.10); adjusted OR (95% CI) = 2.56 (1.22–5.35), respectively]. It is necessary to reduce “perceived severity” among in-home screeners to increase dementia screening participants. Show more

Keywords: Belief, dementia, intention, screening

DOI: 10.3233/JAD-171177

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1651-1661, 2018

Authors: Cam, Morgane | Durieu, Emilie | Bodin, Marion | Manousopoulou, Antigoni | Koslowski, Svenja | Vasylieva, Natalia | Barnych, Bogdan | Hammock, Bruce D. | Bohl, Bettina | Koch, Philipp | Omori, Chiori | Yamamoto, Kazuo | Hata, Saori | Suzuki, Toshiharu | Karg, Frank | Gizzi, Patrick | Erakovic Haber, Vesna | Bencetic Mihaljevic, Vlatka | Tavcar, Branka | Portelius, Erik | Pannee, Josef | Blennow, Kaj | Zetterberg, Henrik | Garbis, Spiros D. | Auvray, Pierrick | Gerber, Hermeto | Fraering, Jeremy | Fraering, Patrick C. | Meijer, Laurent

Article Type: Research Article

Abstract: Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42 /Aβ43 over Aβ40 , and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the ‘human chemical exposome’ contains products able to favor the production of Aβ42 /Aβ43 over Aβ40 and shorter Aβs. To detect such products, …we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ42 /Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42 /Aβ43 . Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42 /Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42 /Aβ43 peptides, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD. Show more

Keywords: Aβ38, Aβ40, Aβ42, Aβ43, Aβ42/Aβ40 ratio, aftins, Alzheimer’s disease, alzheimerogen, amyloid-β, amyloid-β protein precursor, fipronil, γ-secretase, human chemical exposome, pesticides, phenylpyrazoles, prevention, pyrazoles, triazines

DOI: 10.3233/JAD-170875

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1663-1681, 2018

Authors: Piaceri, Irene | Imperiale, Daniele | Ghidoni, Enrico | Atzori, Cristiana | Bagnoli, Silvia | Ferrari, Camilla | Ungari, Silvana | Ambrogio, Luca | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Research Article

Abstract: Background: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer’s disease or psychiatric disorders, jeopardizing care and research. Objective: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer’s disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein). Methods: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s. Results: Four patients out of the 63 studied (4/63, …6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature. Conclusion: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, GRN, mutation

DOI: 10.3233/JAD-170989

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1683-1689, 2018

Authors: Lee, Christopher M. | Jacobs, Heidi I.L. | Marquié, Marta | Becker, John A. | Andrea, Nicolas V. | Jin, David S. | Schultz, Aaron P. | Frosch, Matthew P. | Gómez-Isla, Teresa | Sperling, Reisa A. | Johnson, Keith A.

Article Type: Research Article

Abstract: Background: On target 18 F-Flortaucipir (FTP) binding of Alzheimer’s disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography. Objective: We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition. Methods: FTP race differences in 147 Harvard Aging Brain Study participants …(23 B/AA, 124W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residuals and unadjusted HC SUVR to race, cognition and amyloid. All analyses were covaried for age, sex, education and amyloid deposition, and Bonferroni-corrected for multiple comparisons. Results: B/AA individuals had elevated CP and HC SUVR (p  < 0.007), whereas other ROI SUVR and HC SUVR covaried for CP SUVR did not show race differences (p  > 0.05). CP SUVR was associated with HC SUVR (p  < 10–14 ), but with no other ROI SUVR (p  > 0.05). When adjusting HC SUVR for CP SUVR, no race differences in residual HC SUVR were detected, and relationships with amyloid and memory became apparent. Conclusion: Melanocyte FTP binding may account partially for high CP signal. This off-target binding affects mainly HC FTP measurements, which should be interpreted with caution. Show more

Keywords: Alzheimer’s disease, choroid plexus, off-target binding, melanin, race, tau PET

DOI: 10.3233/JAD-170840

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1691-1702, 2018

Authors: Alves, Luísa | Cardoso, Sandra | Maroco, João | de Mendonça, Alexandre | Guerreiro, Manuela | Silva, Dina

Article Type: Research Article

Abstract: Background: Although the diagnosis of mild cognitive impairment (MCI) corresponds to a condition likely to progress to dementia, essentially Alzheimer’s disease, longitudinal studies have shown that some patients may not convert to dementia and maintain the diagnosis of MCI even after many years. Objectives: To determine whether patients that maintain the diagnosis of MCI in the long term (10 years) are really stable or just declining slowly, and to identify clinical and neuropsychological characteristics associated with long-term stability. Methods: The Cognitive Complaints Cohort (CCC) was searched for MCI cases who maintained that diagnosis for at least …10 years. For each long-term-stable MCI patient, two MCI patients that converted to dementia during follow-up, matched for age and education, were selected from the same database. The baseline and last neuropsychological evaluations for long-term-stable MCI and converter MCI were compared. Baseline neuropsychological predictors of long-term stability were searched for. Results: Long-term-stable MCI (n  = 22) and converter MCI (n  = 44) patients did not differ in terms of gender distribution, education, age at first assessment and time between symptom onset and first evaluation. Time of follow-up was on average 11 years for long-term-stable MCI and 3 years for converter MCI. The baseline and follow-up neuropsychological tests were not significantly different in long-term-stable MCI patients, whereas a general decline was observed in converter MCI patients. Higher scores on one memory test, the Word Delayed Total Recall, and on the non-verbal abstraction test, Raven’s Progressive Matrices, at the baseline predicted long-term (10 years) clinical stability. Conclusions: Some patients with MCI remain clinically and neuropsychologically stable for a decade. Better performances at baseline in memory and non-verbal abstraction tests predict long-term stability. Show more

Keywords: Amnestic, follow-up, long-term, mild cognitive impairment, neuropsychological tests, prediction, stability

DOI: 10.3233/JAD-171034

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1703-1711, 2018

Authors: Tetzloff, Katerina A. | Graff-Radford, Jonathan | Martin, Peter R. | Tosakulwong, Nirubol | Machulda, Mary M. | Duffy, Joseph R. | Clark, Heather M. | Senjem, Matthew L. | Schwarz, Christopher G. | Spychalla, Anthony J. | Drubach, Daniel A. | Jack Jr., Clifford R. | Lowe, Val J. | Josephs, Keith A. | Whitwell, Jennifer L.

Article Type: Research Article

Abstract: Background: Despite common pathology, Alzheimer’s disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD. Objective: To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA). Methods: Eighteen PCA and 19 lvPPA subjects that showed amyloid-β deposition on PET underwent tau-PET imaging …with [18 F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations. Results: Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates. Conclusion: Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition. Show more

Keywords: Aphasia, dementia, neuroimaging, positron emission tomography

DOI: 10.3233/JAD-170740

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1713-1724, 2018