Journal of Alzheimer's Disease - Volume 77, issue 4

Authors: Talan, Jamie

Article Type: Obituary

DOI: 10.3233/JAD-201108

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1369-1371, 2020

Authors: Grossmann, Klaus

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a multifactorial syndrome with a plethora of progressive, degenerative changes in the brain parenchyma, but also in the cerebrovascular and hemostatic system. A therapeutic approach for AD is reviewed, which is focused on the role of amyloid–β protein (Aβ) and fibrin in triggering intra-brain vascular dysfunction and connected, cognitive decline. It is proposed that direct oral anticoagulants (DOACs) counteract Aβ-induced pathological alterations in cerebral blood vessels early in AD, a condition, known as cerebral amyloid angiopathy (CAA). By inhibiting thrombin for fibrin formation, anticoagulants can prevent accumulations of proinflammatory thrombin and fibrin, and deposition of degradation-resistant, …Aβ-containing fibrin clots. These fibrin–Aβ clots are found in brain parenchyma between neuron cells, and in and around cerebral blood vessels in areas of CAA, leading to decreased cerebral blood flow. Consequently, anticoagulant treatment could reduce hypoperfusion and restricted supply of brain tissue with oxygen and nutrients. Concomitantly, hypoperfusion-enhanced neurodegenerative processes, such as progressive Aβ accumulation via synthesis and reduced perivascular clearance, neuroinflammation, and synapse and neuron cell loss, could be mitigated. Given full cerebral perfusion and reduced Aβ- and fibrin-accumulating and inflammatory milieu, anticoagulants could be able to decrease vascular-driven progression in neurodegenerative and cognitive changes, present in AD, when treated early, therapeutically, or prophylactically. Show more

Keywords: Alzheimer’s disease, anticoagulant, brain perfusion, cerebral amyloid–β angiopathy, fibrin, neuroinflammation, thrombin, vascular dysfunction

DOI: 10.3233/JAD-200610

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1373-1382, 2020

Authors: Gelman, Simon | Palma, Jonathan | Ghavami, Afshin

Article Type: Short Communication

Abstract: The timing of action potentials arrival at synaptic terminals partially determines integration of synaptic inputs and is important for information processing in the CNS. Therefore, axonal conduction velocity (VC ) is a salient parameter, influencing the timing of synaptic inputs. Even small changes in VC may disrupt information coding in networks requiring accurate timing. We recorded compound action potentials in hippocampal slices to measure VC in three mouse models of Alzheimer’s disease. We report an age-dependent reduction in VC in area CA1 in two amyloid-β precursor protein transgenic mouse models, line 41 and APP/PS1, and in a …tauopathy model, rTg4510. Show more

Keywords: Amyloidosis, APP/PS1, compound action potentials, electrophysiology, Line 41, rTg4510, tauopathy

DOI: 10.3233/JAD-200661

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1383-1388, 2020

Authors: Wang, Yi | Li, Liyu | Tian, Shuangyue | Wu, Jie | Wang, Zhiwen

Article Type: Research Article

Abstract: Background: Home environment is a core domain in the care of community-dwelling older adults with dementia, but there is no suitable instrument to measure it in China. Objective: To develop and psychometrically test the home environment assessment checklist for community-dwelling older adults with dementia. Methods: A three-step process was performed to develop and test this instrument: 1) based on the evidence-based theory, the checklist was summarized as the main points of evidence from living environment settings among older adults with dementia, 2) the draft tool was assigned to an iterative process of evaluation by a panel …of examiners consisting of experts from treatment, nursing and caring, people with dementia and their caregivers, 3) inter-rater reliability and internal consistency were calculated with a sample of 348 caregivers of the older adults with dementia. Results: The HEAC consisted of 71 items in domains addressing safety, stability and familiarity, visual cues, and sensory stimulation. Psychometric evaluation showed that this tool demonstrated sound reliability and validity. Content validity was 0.969 which was established by a panel of experts (n  = 10). Inter-rater reliability of two researchers was 0.978, and 0.848 for researchers and caregivers. Test-retest reliability was excellent (ICC = 0.757–0.877) in community-dwelling older adults with dementia 2 week apart. Conclusion: The HEAC is a new tool to help collect the reliable information on the barriers and facilitators of home environment for community-dwelling older adults with dementia and to precipitate the home modification process to improve the quality of care for people with dementia and their caregivers in daily life. Show more

Keywords: Checklist, dementia, home environment, older adults, psychometrics test

DOI: 10.3233/JAD-200241

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1389-1396, 2020

Authors: Van Kolen, Kristof | Malia, Thomas J. | Theunis, Clara | Nanjunda, Rupesh | Teplyakov, Alexey | Ernst, Robin | Wu, Sheng-Jiun | Luo, Jinquan | Borgers, Marianne | Vandermeeren, Marc | Bottelbergs, Astrid | Wintmolders, Cindy | Lacy, Eilyn | Maurin, Hervé | Larsen, Peter | Willems, Roland | Van De Casteele, Tom | Triana-Baltzer, Gallen | Slemmon, Randy | Galpern, Wendy | Trojanowski, John Q. | Sun, Hong | Mercken, Marc H.

Article Type: Research Article

Abstract: Background: As a consequence of the discovery of an extracellular component responsible for the progression of tau pathology, tau immunotherapy is being extensively explored in both preclinical and clinical studies as a disease modifying strategy for the treatment of Alzheimer’s disease. Objective: Describe the characteristics of the anti-phospho (T212/T217) tau selective antibody PT3 and its humanized variant hPT3. Methods: By performing different immunization campaigns, a large collection of antibodies has been generated and prioritized. In depth, in vitro characterization using surface plasmon resonance, phospho-epitope mapping, and X-ray crystallography experiments were performed. Further characterization involved immunohistochemical …staining on mouse- and human postmortem tissue and neutralization of tau seeding by immunodepletion assays. Results and Conclusion: Various in vitro experiments demonstrated a high intrinsic affinity for PT3 and hPT3 for AD brain-derived paired helical filaments but also to non-aggregated phospho (T212/T217) tau. Further functional analyses in cellular and in vivo models of tau seeding demonstrated almost complete depletion of tau seeds in an AD brain homogenate. Ongoing trials will provide the clinical evaluation of the tau spreading hypothesis in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, immunotherapy, monoclonal antibodies, tau protein

DOI: 10.3233/JAD-200544

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1397-1416, 2020

Authors: Triana-Baltzer, Gallen | Van Kolen, Kristof | Theunis, Clara | Moughadam, Setareh | Slemmon, Randy | Mercken, Marc | Galpern, Wendy | Sun, Hong | Kolb, Hartmuth

Article Type: Research Article

Abstract: Background: Early and accurate detection and staging is critical to managing Alzheimer’s disease (AD) and supporting clinical trials. Cerebrospinal fluid (CSF) biomarkers for amyloid-β peptides, tau species, and various neurodegenerative and inflammatory analytes are leading the way in this regard, yet there is room for improved sensitivity and specificity. In particular tau is known to be present in many different fragments, conformations, and post-translationally modified forms. While the exact tau species that might best reflect AD pathology is unknown, a growing body of evidence suggests that forms with high levels of phosphorylation in the mid-region may be especially enriched in …AD. Objective: Develop an assay for measuring p217tau in CSF. Methods: Here we describe the development and validation of a novel sELISA for measuring CSF tau species containing phosphorylation at threonines 212 & 217, aka p217 + tau, using the PT3 antibody. Results: While the analyte is present at extremely low levels the assay is sufficiently sensitive and specific to quantitate p217 + tau with excellent precision, accuracy, and dilution linearity, allowing good differentiation between diagnostic subgroups. The p217 + tau measurements appear to track AD pathology better than the commonly used p181tau epitope, suggesting superior diagnostic and staging performance. Finally, the assay can also be configured to differentiate antibody-bound versus antibody-free tau, and therefore can be used to measure target engagement by p217 + tau-targeting immunotherapeutics. Conclusion: The assay for measuring p217 + tau described here is highly sensitive, accurate, precise, dilution linear, and shows good potential for identifying and staging AD. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, p212, p217, phosphorylation, tau

DOI: 10.3233/JAD-200463

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1417-1430, 2020

Authors: Montandon, Marie-Louise | Herrmann, François R. | Garibotto, Valentina | Rodriguez, Cristelle | Haller, Sven | Giannakopoulos, Panteleimon

Article Type: Research Article

Abstract: Background: The cognitive trajectories in normal aging may be affected by medial temporal atrophy (MTA) and amyloid burden, as well as vascular pathologies such as cortical microbleeds (CMB) and white matter hyperintensities (WMH). Objective: We addressed here the role of imaging markers in their prediction in a real-world situation. Methods: We performed a 4.5-year longitudinal study in 90 older community-dwellers coupling two neuropsychological assessments, MTA estimated with the Schelten’s scale, number of CMB, and WMH evaluated with the Fazekas score at inclusion and follow-up, visual rating of amyloid PET and glucose hypometabolism at follow-up, and APOE …genotyping. Regression models were built to explore the association between the continuous cognitive score (CCS) and imaging parameters. Results: The number of strictly lobar CMB at baseline (4 or more) was related to a 5.5-fold increase of the risk of cognitive decrement. This association persisted in multivariable models explaining 10.6% of the CCS decrease variance. MTA, and Fazekas score at baseline and amyloid positivity or abnormal FDG PET, were not related to the cognitive outcome. The increase of right MTA at follow-up was the only correlate of CCS decrease both in univariate and multivariable models explaining 9.2% of its variance. Conclusion: The present data show that the accumulation of more than four CMB is associated with significant cognitive decrement over time in highly educated elderly persons. They also reveal that the progressive deterioration of cognitive performance within the age-adjusted norms is also related to the increase of visually assessed MTA. Show more

Keywords: Atrophy, cognition, imaging markers, medial temporal lobe, microbleeds, normal aging

DOI: 10.3233/JAD-200559

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1431-1442, 2020

Authors: Müller, Theresa | Payton, Nicola M. | Kalpouzos, Grégoria | Jessen, Frank | Grande, Giulia | Bäckman, Lars | Laukka, Erika J.

Article Type: Research Article

Abstract: Background: Although associated with dementia and cognitive impairment, microstructural white matter integrity is a rarely used marker of preclinical dementia. Objective: We aimed to evaluate the individual and combined effects of multiple markers, with special focus on microstructural white matter integrity, in detecting individuals with increased dementia risk. Methods: A dementia-free subsample (n  = 212, mean age = 71.33 years) included in the population-based Swedish National Study on Aging and Care (SNAC-K) underwent magnetic resonance imaging (T1-weighted, fluid-attenuated inversion recovery, diffusion tensor imaging), neuropsychological testing (perceptual speed, episodic memory, semantic memory, letter and category fluency), and genotyping (APOE ). …Incident dementia was assessed during six years of follow-up. Results: A global model (global cognition, APOE , total brain tissue volume: AUC = 0.920) rendered the highest predictive value for future dementia. Of the models based on specific markers, white matter integrity of the forceps major tract was included in the most predictive model, in combination with perceptual speed and hippocampal volume (AUC = 0.911). Conclusion: Assessment of microstructural white matter integrity may improve the early detection of dementia, although the added benefit in this study was relatively small. Show more

Keywords: APOE , cognition, diffusion tensor imaging, magnetic resonance imaging, preclinical dementia, white matter

DOI: 10.3233/JAD-200445

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1443-1453, 2020

Authors: Santangelo, Roberto | Huang, Su-Chun | Bernasconi, Maria Paola | Falautano, Monica | Comi, Giancarlo | Magnani, Giuseppe | Leocani, Letizia

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathological hallmarks were found in retinas of AD patients. Several studies showed a significant reduction of neuro-retina thickness measured through optical coherence tomography (OCT) in AD patients, but possible correlations between retina morphology, cognition, and cerebrospinal fluid (CSF) AD biomarkers (Aβ 42 , t-tau, and p-tau) have been poorly investigated so far. Objective: In the present cross-sectional study, we measured the thickness of neuro-retinal layers through OCT searching for possible correlations with patients’ cognitive performances and CSF AD biomarkers. Methods: 137 consecutive subjects [43 with AD, 37 with mild cognitive impairment (MCI), …and 57 healthy controls (HC) ], received an OCT scan acquisition to measure the peripapillary retinal nerve fiber layer (RNFL) thickness. In a subsample of 21 AD, 18 MCI, and 18 HC, the macular volume of ganglion cell layer (GCL), inner plexiform layer (IPL), and inner nuclear layer was computed. A comprehensive neuropsychological assessment and CSF AD biomarkers’ concentrations were available in AD and MCI patients. Results: Peripapillary RNFL, global, and in superior quadrant was significantly thinner in AD and MCI patients when compared to HC, while macular GCL volume was significantly reduced only in AD. RNFL thickness in nasal and inferior quadrants was correlated with single CSF AD biomarker concentrations, but no differences were found in retina morphology depending on the presence of a CSF profile typical for AD. Memory performances were positively associated with GCL and IPL volume. Conclusion: Our findings might propose OCT as a reliable and easy to handle tool able to detect neuro-retinal atrophy in AD in relation with cognitive performances. Show more

Keywords: Alzheimer’s disease, ganglion cell layer, inner plexiform layer, mild cognitive impairment, neuro-retina, optical coherence tomography, retinal nerve fiber layer

DOI: 10.3233/JAD-200043

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1455-1468, 2020

Authors: Olive, Claudia | Ibanez, Laura | Farias, Fabiana H. Geraldo | Wang, Fengxian | Budde, John P. | Norton, Joanne B. | Gentsch, Jen | Morris, John C. | Li, Zeran | Dube, Umber | Del-Aguila, Jorge | Bergmann, Kristy | Bradley, Joseph | Benitez, Bruno A. | Harari, Oscar | Fagan, Anne | Ances, Beau | Cruchaga, Carlos | Fernandez, Maria Victoria

Article Type: Research Article

Abstract: Background: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer’s disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. Objective: In this study, we aim to evaluate the association of rare coding variants in PLCG2 , ABI3 , and TREM2 with LOAD risk and their effect at different time points of the disease. Methods: We used a European American cohort to assess the association of the variants …prior onset (using CSF Aβ42 , tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). Results: We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes. Conclusion: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease. Show more

Keywords: ABI3 , endophenotypes, late onset Alzheimer’s disease, PLCG2 , progression, TREM2

DOI: 10.3233/JAD-200019

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1469-1482, 2020