Journal of Alzheimer's Disease - Volume 86, issue 3

Authors: Liu, Ziming | Paek, Eun Jin | Yoon, Si On | Casenhiser, Devin | Zhou, Wenjun | Zhao, Xiaopeng

Article Type: Research Article

Abstract: Background: People with Alzheimer’s disease (AD) often demonstrate difficulties in discourse production. Referential communication tasks (RCTs) are used to examine a speaker’s capability to select and verbally code the characteristics of an object in interactive conversation. Objective: In this study, we used contextualized word representations from Natural language processing (NLP) to evaluate how well RCTs are able to distinguish between people with AD and cognitively healthy older adults. Methods: We adapted machine learning techniques to analyze manually transcribed speech transcripts in an RCT from 28 older adults, including 12 with AD and 16 cognitively healthy older …adults. Two approaches were applied to classify these speech transcript samples: 1) using clinically relevant linguistic features, 2) using machine learned representations derived by a state-of-art pretrained NLP transfer learning model, Bidirectional Encoder Representation from Transformer (BERT) based classification model. Results: The results demonstrated the superior performance of AD detection using a designed transfer learning NLP algorithm. Moreover, the analysis showed that transcripts of a single image yielded high accuracies in AD detection. Conclusion: The results indicated that RCT may be useful as a diagnostic tool for AD, and that the task can be simplified to a subset of images without significant sacrifice to diagnostic accuracy, which can make RCT an easier and more practical tool for AD diagnosis. The results also demonstrate the potential of RCT as a tool to better understand cognitive deficits from the perspective of discourse production in people with AD. Show more

Keywords: Alzheimer’s disease, early diagnosis, natural language processing, transfer learning

DOI: 10.3233/JAD-215137

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1385-1398, 2022

Authors: Hua, Xue | Church, Kevin | Walker, William | L’Hostis, Philippe | Viardot, Geoffrey | Danjou, Philippe | Hendrix, Suzanne | Moebius, Hans J.

Article Type: Research Article

Abstract: Background: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer’s disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss. Objective: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton. Methods: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n  = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects …(n  = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n  = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement. Results: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p  = 0.027; n  = 7 at 40 mg fosgonimeton versus n  = 4 placebo). Conclusion: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects. Show more

Keywords: ATH-1001, ATH-1017, Alzheimer’s disease, dementia, fosgonimeton, hepatocyte growth factor, electroencephalography, event-related potentials, P300 component, neurotrophic factor

DOI: 10.3233/JAD-215511

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1399-1413, 2022

Authors: Chan, Carol K. | Pettigrew, Corinne | Soldan, Anja | Zhu, Yuxin | Wang, Mei-Cheng | Albert, Marilyn | Rosenberg, Paul B. | and the BIOCARD Research Team

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) among cognitively normal older adults are increasingly recognized as risk factors for cognitive decline and impairment. However, the underlying mechanisms remain unclear. Objective: To examine whether biomarkers of Alzheimer’s disease (amyloid burden) and cerebrovascular disease (white matter hyperintensity (WMH) volume) modify the association between NPS and cognitive decline among cognitively unimpaired older adults. Methods: Analyses included 193 cognitively unimpaired participants (M age = 70 years) from the BIOCARD study, including 148 with PET amyloid and WMH biomarker data. NPS were measured with Neuropsychiatric Inventory and Geriatric Depression Scale scores. Linear mixed effects models …were used to examine the association between baseline NPS and longitudinal cognitive trajectories (M follow-up = 3.05 years), using separate models for global, episodic memory, and executive function cognitive composite scores. In a subset of individuals with biomarker data, we evaluated whether WMH or cortical amyloid burden modified the relationship between NPS and cognitive change (as indicated by the NPS×biomarker×time interactions). Results: Higher baseline NPS were associated with lower executive function scores, but not a faster rate of decline in executive function. NPS symptoms were unrelated to the global or episodic memory composite scores, and there was little evidence of a relationship between NPS symptoms and cognitive change over time. The associations between NPS and cognitive decline did not differ by amyloid or WMH burden, and NPS were unrelated to amyloid and WMH burden. Conclusion: These results suggest that the effect of neuropsychiatric symptoms on executive dysfunction may occur through mechanisms outside of amyloid and cerebrovascular disease. Show more

Keywords: Alzheimer’s disease, amyloid, depression, mild behavioral impairment, neuropsychiatric symptoms, white matter hyperintensities

DOI: 10.3233/JAD-215267

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1415-1426, 2022

Authors: Tsamou, Maria | Carpi, Donatella | Pistollato, Francesca | Roggen, Erwin L.

Article Type: Research Article

Abstract: Background: A complex network of aging-related homeostatic pathways that are sensitive to further deterioration in the presence of genetic, systemic, and environmental risk factors, and lifestyle, is implicated in the pathogenesis of progressive neurodegenerative diseases, such as sporadic (late-onset) Alzheimer’s disease (sAD). Objective: Since sAD pathology and neurotoxicity share microRNAs (miRs) regulating common as well as overlapping pathological processes, environmental neurotoxic compounds are hypothesized to exert a risk for sAD initiation and progression. Methods: Literature search for miRs associated with human sAD and environmental neurotoxic compounds was conducted. Functional miR analysis using PathDip was performed to …create miR-target interaction networks. Results: The identified miRs were successfully linked to the hypothetical starting point and key events of the earlier proposed tau-driven adverse outcome pathway toward memory loss. Functional miR analysis confirmed most of the findings retrieved from literature and revealed some interesting findings. The analysis identified 40 miRs involved in both sAD and neurotoxicity that dysregulated processes governing the plausible adverse outcome pathway for memory loss. Conclusion: Creating miR-target interaction networks related to pathological processes involved in sAD initiation and progression, and environmental chemical-induced neurotoxicity, respectively, provided overlapping miR-target interaction networks. This overlap offered an opportunity to create an alternative picture of the mechanisms underlying sAD initiation and early progression. Looking at initiation and progression of sAD from this new angle may open for new biomarkers and novel drug targets for sAD before the appearance of the first clinical symptoms. Show more

Keywords: Adverse outcome pathway, Alzheimer’s disease, key events, miRs, neurotoxicity

DOI: 10.3233/JAD-215434

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1427-1457, 2022

Authors: Aksnes, Mari | Aass, Hans Christian D. | Tiiman, Ann | Terenius, Lars | Bogdanović, Nenad | Vukojević, Vladana | Knapskog, Anne-Brita

Article Type: Research Article

Abstract: Background: Neuroinflammation is a central component of Alzheimer’s disease (AD) and correlates closely with amyloid pathology. Markers of inflammation such as cytokines, and amyloidogenic aggregates, so-called nanoplaques, are both promising biomarker candidates for AD. We have previously shown that there is a relationship between the levels of nanoplaques and cytokines in cerebrospinal fluid, but it is unknown whether this association extends to serum. Objective: Investigate in a naturalistic memory clinic cohort whether the associations between nanoplaques and cytokines in the cerebrospinal fluid extends to serum. Methods: We collected serum from 49 patients assessed for cognitive complaints …at the Oslo University Hospital Memory Clinic (15 with clinical AD). We assessed the levels of serum nanoplaques with the novel Thioflavin-T fluorescence correlation spectroscopy (ThT-FCS) assay. Serum levels of nine cytokines (eotaxin-1, granulocyte colony-stimulating factor [G-CSF], interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1 (MCP-1), gamma induced protein 10 (IP-10), macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a multiplex assay and read on a Luminex IS 200 instrument. Results: Serum nanoplaques were not increased in clinical AD patients compared to non-AD memory clinic patients and nanoplaques were not associated with any cytokines. The cytokines IL-8 and G-CSF were increased in patients with clinical AD compared to non-AD patients. Conclusion: In this small pilot study, serum nanoplaques were not associated with serum cytokines. Nanoplaque levels could not be used to separate clinical AD patients from non-AD patients in this unselected memory clinic cohort. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid-β peptide, biomarkers, cytokines, fluorescence, serum, Thioflavin T

DOI: 10.3233/JAD-215504

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1459-1470, 2022

Authors: Kundu, Payel | Zimmerman, Benjamin | Quinn, Joseph F. | Kaye, Jeffrey | Mattek, Nora | Westaway, Shawn K. | Raber, Jacob

Article Type: Research Article

Abstract: Background: α-klotho might play a role in neurodegenerative diseases. Objective: To determine levels of α-klotho and apoE in serum and cerebrospinal fluid (CSF) samples and their relationship with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Methods: All subjects were between age 39 to 83+ (n  = 94). CDR and MMSE were administered to all participants. CSF was collected in the early afternoon by lumbar puncture. Results: Serum and CSF levels of α-klotho are positively correlated and both predict scores on the MMSE and CDR, regardless of sex or apoE4 status. …Conclusion: Our results demonstrate that α-klotho may be an important biomarker of cognitive health and neurodegeneration, and that relatively non-invasive sampling of α-klotho from serum is likely highly reflective of CSF levels. Show more

Keywords: α-klotho, apoE, cerebrospinal fluid, Clinical Dementia Rating, Mini-Mental State Examination, serum

DOI: 10.3233/JAD-215719

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1471-1481, 2022

Article Type: Correction

DOI: 10.3233/JAD-229002

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1483-1483, 2022