Journal of Alzheimer's Disease - Volume 69, issue 1

Authors: Frisoni, Giovanni B. | Blin, Olivier | Bordet, Regis

Article Type: Editorial

DOI: 10.3233/JAD-190267

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 1-2, 2019

Authors: Marizzoni, Moira | Ferrari, Clarissa | Jovicich, Jorge | Albani, Diego | Babiloni, Claudio | Cavaliere, Libera | Didic, Mira | Forloni, Gianluigi | Galluzzi, Samantha | Hoffmann, Karl-Titus | Molinuevo, José Luis | Nobili, Flavio | Parnetti, Lucilla | Payoux, Pierre | Ribaldi, Federica | Rossini, Paolo Maria | Schönknecht, Peter | Salvatore, Marco | Soricelli, Andrea | Hensch, Tilman | Tsolaki, Magda | Visser, Pieter Jelle | Wiltfang, Jens | Richardson, Jill C. | Bordet, Régis | Blin, Olivier | Frisoni, Giovanni B. | The PharmaCog Consortium

Article Type: Research Article

Abstract: Background: Early Alzheimer’s disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. Objective: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. Methods: APOE ɛ 4 specific CSF Aβ42 /P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42 /P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes …in ADAS-cog13, 2) with Aβ42 /P-tau status, time, and Aβ42 /P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. Results: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p ≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction). Conclusion: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs. Show more

Keywords: Alzheimer’s disease, biomarkers, clinical trial, magnetic resonance imaging, mild cognitive impairment, precision medicine

DOI: 10.3233/JAD-180152

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 3-14, 2019

Authors: Jovicich, Jorge | Babiloni, Claudio | Ferrari, Clarissa | Marizzoni, Moira | Moretti, Davide V. | Del Percio, Claudio | Lizio, Roberta | Lopez, Susanna | Galluzzi, Samantha | Albani, Diego | Cavaliere, Libera | Minati, Ludovico | Didic, Mira | Fiedler, Ute | Forloni, Gianluigi | Hensch, Tilman | Molinuevo, José Luis | Bartrés Faz, David | Nobili, Flavio | Orlandi, Daniele | Parnetti, Lucilla | Farotti, Lucia | Costa, Cinzia | Payoux, Pierre | Rossini, Paolo Maria | Marra, Camillo | Schönknecht, Peter | Soricelli, Andrea | Noce, Giuseppe | Salvatore, Marco | Tsolaki, Magda | Visser, Pieter Jelle | Richardson, Jill C. | Wiltfang, Jens | Bordet, Régis | Blin, Olivier | Frisoniand, Giovanni B. | and the PharmaCog Consortium

Article Type: Research Article

Abstract: Auditory “oddball” event-related potentials (aoERPs), resting state functional magnetic resonance imaging (rsfMRI) connectivity, and electroencephalographic (rsEEG) rhythms were tested as longitudinal functional biomarkers of prodromal Alzheimer’s disease (AD). Data were collected at baseline and four follow-ups at 6, 12, 18, and 24 months in amnesic mild cognitive impairment (aMCI) patients classified in two groups: “positive” (i.e., “prodromal AD”; n  = 81) or “negative” (n  = 63) based on a diagnostic marker of AD derived from cerebrospinal samples (Aβ 42 /P-tau ratio). A linear mixed model design was used to test functional biomarkers for Group, Time, and Group×Time effects adjusted by nuisance covariates …(only data until conversion to dementia was used). Functional biomarkers that showed significant Group effects (“positive” versus “negative”, p  < 0.05) regardless of Time were 1) reduced rsfMRI connectivity in both the default mode network (DMN) and the posterior cingulate cortex (PCC), both also giving significant Time effects (connectivity decay regardless of Group); 2) increased rsEEG source activity at delta (<4 Hz) and theta (4–8 Hz) rhythms and decreased source activity at low-frequency alpha (8–10.5 Hz) rhythms; and 3) reduced parietal and posterior cingulate source activities of aoERPs. Time×Group effects showed differential functional biomarker progression between groups: 1) increased rsfMRI connectivity in the left parietal cortex of the DMN nodes, consistent with compensatory effects and 2) increased limbic source activity at theta rhythms. These findings represent the first longitudinal characterization of functional biomarkers of prodromal AD relative to “negative” aMCI patients based on 5 serial recording sessions over 2 years. Show more

Keywords: Alpha rhythms, amnesic mild cognitive impairment, biomarkers, clinical trial, electroencephalography, functional magnetic resonance imaging, oddball event-related potentials, PharmaCog project, prodromal Alzheimer’s disease, resting state

DOI: 10.3233/JAD-180158

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 15-35, 2019

Authors: Albani, Diego | Marizzoni, Moira | Ferrari, Clarissa | Fusco, Federica | Boeri, Lucia | Raimondi, Ilaria | Jovicich, Jorge | Babiloni, Claudio | Soricelli, Andrea | Lizio, Roberta | Galluzzi, Samantha | Cavaliere, Libera | Didic, Mira | Schönknecht, Peter | Molinuevo, José Luis | Nobili, Flavio | Parnetti, Lucilla | Payoux, Pierre | Bocchio, Luisella | Salvatore, Marco | Rossini, Paolo Maria | Tsolaki, Magda | Visser, Pieter Jelle | Richardson, Jill C. | Wiltfang, Jens | Bordet, Régis | Blin, Olivier | Forloni, Gianluigi | Frisoni, Giovanni B. | PharmaCog Consortium

Article Type: Research Article

Abstract: It is an open issue whether blood biomarkers serve to diagnose Alzheimer’s disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as “positive” (i.e., “prodromal AD” n = 76) or “negative” (n = 52) based on a diagnostic cut-off of Aβ42 /P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at …two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aβ42 , Aβ40 ) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the “positive” (i.e., prodromal AD) and “negative” groups at baseline. In contrast, plasma Aβ42 showed a greater reduction over time in the prodromal AD than the “negative” aMCI group (p = 0.048), while CLU and Aβ40 increased, but similarly in the two groups. Furthermore, plasma Aβ42 correlated with the ADAS-Cog13 score both in aMCI patients as a whole and the prodromal AD group alone. Finally, CLU correlated with the ADAS-Cog13 only in the whole aMCI group, and no association with ADAS-Cog13 was found for Aβ40 . In conclusion, plasma Aβ42 showed disease progression-related features in aMCI patients with prodromal AD. Show more

Keywords: Amnesic mild cognitive impairment, amyloid-beta peptide, biomarkers, clinical trial, clusterin, PharmaCog project, prodromal Alzheimer’s disease

DOI: 10.3233/JAD-180321

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 37-48, 2019

Authors: Marizzoni, Moira | Ferrari, Clarissa | Macis, Ambra | Jovicich, Jorge | Albani, Diego | Babiloni, Claudio | Cavaliere, Libera | Didic, Mira | Forloni, Gianluigi | Galluzzi, Samantha | Hoffmann, Karl-Titus | Molinuevo, José Luis | Nobili, Flavio | Parnetti, Lucilla | Payoux, Pierre | Pizzini, Francesca | Rossini, Paolo Maria | Salvatore, Marco | Schönknecht, Peter | Soricelli, Andrea | Del Percio, Claudio | Hensch, Tilman | Hegerl, Ulrich | Tsolaki, Magda | Visser, Pieter Jelle | Wiltfang, Jens | Richardson, Jill C. | Bordet, Régis | Blin, Olivier | Frisoni, Giovanni B. | The PharmaCog Consortium

Article Type: Research Article

Abstract: Background: Assessment of human brain atrophy in temporal regions using magnetic resonance imaging (MRI), resting state functional MRI connectivity in the left parietal cortex, and limbic electroencephalographic (rsEEG) rhythms as well as plasma amyloid peptide 42 (Aβ42 ) has shown that each is a promising biomarker of disease progression in amnestic mild cognitive impairment (aMCI) patients with prodromal Alzheimer’s disease (AD). However, the value of their combined use is unknown. Objective: To evaluate the association with cognitive decline and the effect on sample size calculation when using a biomarker composite matrix in prodromal AD clinical trials. …Methods: Multicenter longitudinal study with follow-up of 2 years or until development of incident dementia. APOE ɛ 4-specific cerebrospinal fluid (CSF) Aβ42 /P-tau cut-offs were used to identify aMCI with prodromal AD. Linear mixed models were performed 1) with repeated matrix values and time as factors to explain the longitudinal changes in ADAS-cog13, 2) with CSF Aβ42 /P-tau status, time, and CSF Aβ42 /P-tau status×time interaction as factors to explain the longitudinal changes in matrix measures, and 3) to compute sample size estimation for a trial implemented with the selected matrices. Results: The best composite matrix included the MRI volumes of hippocampal dentate gyrus and lateral ventricle. This matrix showed the best sensitivity to track disease progression and required a sample size 31% lower than that of the best individual biomarker (i.e., volume of hippocampal dentate gyrus). Conclusion: Optimal matrices improved the statistical power to track disease development and to measure clinical progression in the short-term period. This might contribute to optimize the design of future clinical trials in MCI. Show more

Keywords: Alzheimer’s disease, biomarker matrices, clinical trial, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-181016

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 49-58, 2019

Authors: Yuan, Jun | Meloni, Bruno P. | Shi, Tianxing | Bonser, Anne | Papadimitriou, John M. | Mastaglia, Frank L. | Zhang, Changqing | Zheng, Minghao | Gao, Junjie

Article Type: Review Article

Abstract: Bone, the major structural scaffold of the human body, has recently been demonstrated to interact with several other organ systems through the actions of bone-derived cells and bone-derived cell secretory proteins. Interestingly, the brain is one organ that appears to fall into this interconnected network. Furthermore, the fact that osteoporosis and Alzheimer’s disease are two common age-related disorders raises the possibility that these two organ systems are interconnected in terms of disease pathogenesis. This review focuses on the latest evidence demonstrating the impact of bone-derived cells and bone-derived proteins on the central nervous system, and on how this may be …relevant in the progression of Alzheimer’s disease and for the identification of novel therapeutic approaches to treat this neurodegenerative disorder. Show more

Keywords: Alzheimer’s disease, bone, mesenchymal stem cells, microglia, osteocalcin

DOI: 10.3233/JAD-181249

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 59-70, 2019

Authors: Martínez, Juan F. | Trujillo, Catalina | Arévalo, Analía | Ibáñez, Agustín | Cardona, Juan F.

Article Type: Review Article

Abstract: The visual experience of objects lies in the ability to perceive and integrate their constitutive features. Conjunctive binding (CB) is the cognitive function that integrates the features of objects as wholes. This review covers the main findings (over the last 10 years) concerning the role of CB in visual working memory (VWM) and cognitive theory, its neural correlates, as well as perspectives for future work. First, we discuss the theoretical cognitive models of CB and how these relate to other cognitive functions. We then integrate neuroimaging evidence with cognitive theory to identify the neural functional network of CB for encoding …and maintenance. Also, we describe the field’s transition from experimental to clinical research, which paves the way for work in the area of VWM binding and aging. Finally, we expose the challenges faced by this field of research and analyze its role in the study of dementia and the construction of neuro-cognitive models of conjunctive binding. Show more

Keywords: Alzheimer’s disease, conjunctive binding, mild cognitive impairment, neuropsychological assessment, working memory

DOI: 10.3233/JAD-181154

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 71-81, 2019

Authors: Alexopoulos, Panagiotis | Thierjung, Nathalie | Economou, Polychronis | Werle, Lukas | Buhl, Felix | Kagerbauer, Simone | Papanastasiou, Anastasios D. | Grimmer, Timo | Gourzis, Philippos | Berthele, Achim | Hemmer, Bernhard | Kübler, Hubert | Martin, Jan | Politis, Antonios | Perneczky, Robert

Article Type: Short Communication

Abstract: Cost- and time-effective markers of Alzheimer’s disease (AD), reliable and feasible at the population level are urgently needed. Soluble amyloid-β protein precursor β (sAβPPβ) in plasma has attracted scientific attention as a potential AD biomarker candidate. Here we report that plasma sAβPPβ levels in patients with AD dementia and typical for AD cerebrospinal fluid (CSF) biomarker profiles (N = 33) are significantly lower (p  < 0.01) than those of cognitively healthy elderly individuals without AD (N = 39), while CSF sAβPPβ levels did not differ between the studied groups. This provides further evidence for the potential of sAβPPβ in plasma as an AD biomarker candidate.

Keywords: Biomarker candidate, NIA-AA research framework diagnostic criteria, soluble amyloid-β protein precursor β

DOI: 10.3233/JAD-181088

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 83-90, 2019

Authors: Raha-Chowdhury, Ruma | Henderson, James W. | Raha, Animesh Alexander | Vuono, Romina | Bickerton, Anastasia | Jones, Elizabeth | Fincham, Robert | Allinson, Kieren | Holland, Anthony | Zaman, Shahid H.

Article Type: Research Article

Abstract: Background: Genetic factors that influence Alzheimer’s disease (AD) risk include mutations in TREM2 and allelic variants of Apolipoprotein E , influencing AD pathology in the general population and in Down syndrome (DS). Evidence shows that dysfunction of the choroid plexus may compromise the blood-cerebrospinal fluid (CSF) barrier, altering secretary, transport and immune function that can affect AD pathology. Objective: To investigate the genotype and phenotype of DS individuals in relation to choroid plexus damage and blood-CSF barrier leakage to identify markers that could facilitate early diagnosis of AD in DS. Methods: To assess allele frequency …and haplotype associations ApoE, Tau, TREM2 , and HLA-DR were analyzed by SNP analysis in DS participants (n  = 47) and controls (n  = 50). The corresponding plasma protein levels were measured by ELISA. Postmortem brains from DS, AD, and age-matched controls were analyzed by immunohistochemistry. Results: Haplotype analysis showed that individuals with Tau H1/H1 and ApoE ɛ 4 genotypes were more prevalent among DS participants with an earlier diagnosis of dementia (17%) compared to H1/H2 haplotypes (6%). Plasma TREM2 levels decreased whereas phospho-tau levels increased with age in DS. In AD and DS brain, insoluble tau and ApoE were found to accumulate in the choroid plexus. Conclusion: Accumulation of tau and ApoE in the choroid plexus may increase the oligomerization rate of Aβ42 and impair tau trafficking, leading to AD pathology. We have identified a high-risk haplotype: ApoE ɛ 4, Tau/H1 , and TREM2/T, that manifests age-related changes potentially opening a window for treatment many years prior to the manifestation of the AD dementia. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, blood-CSF barrier, choroid plexus, Down syndrome, high-risk haplotype, neuroinflammation, tau trafficking, TREM2, white matter tract

DOI: 10.3233/JAD-181179

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 91-109, 2019

Authors: Law, Lena L. | Sprecher, Kate E. | Dougherty, Ryan J. | Edwards, Dorothy F. | Koscik, Rebecca L. | Gallagher, Catherine L. | Carlsson, Cynthia M. | Zetterberg, Henrik | Blennow, Kaj | Asthana, Sanjay | Sager, Mark A. | Hermann, Bruce P. | Johnson, Sterling C. | Cook, Dane B. | Bendlin, Barbara B. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: Background: Previous studies indicate that cardiorespiratory fitness (CRF) and sleep are each favorably associated with Alzheimer’s disease (AD) pathophysiology, including reduced amyloid-β (Aβ) and tau pathology. However, few studies have examined CRF and sleep in the same analysis. Objective: To examine the relationship between sleep and core AD cerebrospinal fluid (CSF) biomarkers among at-risk healthy late-middle-aged adults and determine whether CRF modifies this association. Methods: Seventy-four adults (age = 64.38±5.48, 68.9% female) from the Wisconsin Registry for Alzheimer’s Prevention participated. Sleep was evaluated using the Medical Outcomes Study Sleep Scale, specifically the Sleep Problems Index I (SPI), which …incorporates domains of sleep disturbance, somnolence, sleep adequacy, and shortness of breath. Higher scores indicate greater sleep problems. To assess CRF, participants underwent a graded exercise test. CSF was collected via lumbar puncture, from which Aβ42 , total-tau (t-tau), and phosphorylated-tau (p-tau) were immunoassayed. Regression analyses examined the association between SPI and CSF biomarkers, and the interaction between SPI and CRF on these same biomarkers, adjusting for relevant covariates. Results: Higher SPI scores were associated with greater p-tau (p  = 0.027) and higher t-tau/Aβ42 (p  = 0.021) and p-tau/Aβ42 (p  = 0.009) ratios. Analyses revealed significant SPI*CRF interactions for t-tau (p  = 0.016), p-tau (p  = 0.008), and p-tau/Aβ42 (p  = 0.041); with a trend for t-tau/Aβ42 (p  = 0.061). Specifically, the relationship between poorer sleep and these biomarkers was significant among less fit individuals, but not among those who were more fit. Conclusion: In a late-middle-aged at-risk cohort, CRF attenuated the association between poor sleep and levels of select CSF biomarkers. This suggests fitness may play an important role in preventing AD by protecting against pathology, even in impaired sleep. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, biomarkers, cardiorespiratory fitness, cerebrospinal fluid, sleep, tau protein

DOI: 10.3233/JAD-180291

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 111-121, 2019