Journal of Alzheimer's Disease - Volume 90, issue 2

Authors: Villarejo-Galende, Alberto | García-Arcelay, Elena | Piñol-Ripoll, Gerard | del Olmo-Rodríguez, Antonio | Viñuela, Félix | Boada, Mercè | Franco-Macías, Emilio | Ibañez de la Peña, Almudena | Riverol, Mario | Puig-Pijoan, Albert | Abizanda-Soler, Pedro | Arroyo, Rafael | Baquero-Toledo, Miquel | Feria-Vilar, Inmaculada | Balasa, Mircea | Berbel, Ángel | Rodríguez-Rodríguez, Eloy | Vieira-Campos, Alba | García-Ribas, Guillermo | Rodrigo-Herrero, Silvia | Terrancle, Ángeles | Prefasi, Daniel | Lleó, Alberto | Maurino, Jorge

Article Type: Research Article

Abstract: Background: There is a need to better understand the experience of patients living with Alzheimer's disease (AD) in the early stages. Objective: The aim of the study was to evaluate the perception of quality of life in patients with early-stage AD. Methods: A multicenter, non-interventional study was conducted including patients of 50–90 years of age with prodromal or mild AD, a Mini-Mental State Examination (MMSE) score ≥22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5.–1.0. The Quality of Life in Alzheimer ’s Disease (QoL-AD) questionnaire was used to assess health-related quality of life. A battery …of self-report instruments was used to evaluate different psychological and behavioral domains. Associations between the QoL-AD and other outcome measures were analyzed using Spearman’s rank correlations. Results: A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years and mean disease duration was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1). The mean QoL-AD score was 37.9 (4.5). Eighty-three percent (n = 124) of patients had moderate-to-severe hopelessness, 22.1% (n = 33) had depressive symptoms, and 36.9% (n = 55) felt stigmatized. The quality of life showed a significant positive correlation with self-efficacy and negative correlations with depression, emotional and practical consequences, stigma, and hopelessness. Conclusion: Stigma, depressive symptoms, and hopelessness are frequent scenarios in AD negatively impacting quality of life, even in a population with short disease duration and minimal cognitive impairment. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, magnetic resonance imaging, tau proteins, white matter hyperintensities, white matter lesions

DOI: 10.3233/JAD-220696

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 719-726, 2022

Authors: Sabbir, Mohammad Golam | Speth, Robert C. | Albensi, Benedict C.

Article Type: Research Article

Abstract: Background: Dysfunction of cholinergic neurotransmission is a hallmark of Alzheimer’s disease (AD); forming the basis for using acetylcholine (ACh) esterase (AChE) inhibitors to mitigate symptoms of ACh deficiency in AD. The Cholinergic Receptor Muscarinic 1 (CHRM1) is highly expressed in brain regions impaired by AD. Previous analyses of postmortem AD brains revealed unaltered CHRM1 mRNA expression compared to normal brains. However, the CHRM1 protein level in AD and other forms of dementia has not been extensively studied. Reduced expression of CHRM1 in AD patients may explain the limited clinical efficacy of AChE inhibitors. Objective: To quantify CHRM1 protein …in the postmortem hippocampus and temporal cortex of AD, Parkinson’s disease (PD), and frontotemporal dementia (FTD) patients. Methods: Western blotting was performed on postmortem hippocampus (N  = 19/73/7/9: unaffected/AD/FTD/PD) and temporal cortex (N  = 9/74/27: unaffected/AD/PD) using a validated anti-CHRM1 antibody. Results: Quantification based on immunoblotting using a validated anti-CHRM1 antibody revealed a significant loss of CHRM1 protein level (<50%) in the hippocampi (78% AD, 66% PD, and 85% FTD) and temporal cortices (56% AD and 42% PD) of dementia patients. Loss of CHRM1 in the temporal cortex was significantly associated with early death (<65–75 years) for both AD and PD patients. Conclusion: Severe reduction of CHRM1 in a subset of AD and PD patients can explain the reported low efficacy of AChE inhibitors as a mitigating treatment for dementia patients. Based on this study, it can be suggested that future research should prioritize therapeutic restoration of CHRM1 protein levels in cholinergic neurons. Show more

Keywords: Alzheimer’s disease, β-arrestin, Cholinergic Receptor Muscarinic 1, CHRM1, frontotemporal dementia, Parkinson’s disease, survival

DOI: 10.3233/JAD-220766

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 727-747, 2022

Authors: McClannahan, Katrina S. | Mainardi, Amelia | Luor, Austin | Chiu, Yi-Fang | Sommers, Mitchell S. | Peelle, Jonathan E.

Article Type: Research Article

Abstract: Background: Difficulty understanding speech is a common complaint of older adults. In quiet, speech perception is often assumed to be relatively automatic. However, higher-level cognitive processes play a key role in successful communication in noise. Limited cognitive resources in adults with dementia may therefore hamper word recognition. Objective: The goal of this study was to determine the impact of mild dementia on spoken word recognition in quiet and noise. Methods: Participants were 53–86 years with (n  = 16) or without (n  = 32) dementia symptoms as classified by the Clinical Dementia Rating scale. Participants performed a word identification …task with two levels of word difficulty (few and many similar sounding words) in quiet and in noise at two signal-to-noise ratios, +6 and +3 dB. Our hypothesis was that listeners with mild dementia symptoms would have more difficulty with speech perception in noise under conditions that tax cognitive resources. Results: Listeners with mild dementia symptoms had poorer task accuracy in both quiet and noise, which held after accounting for differences in age and hearing level. Notably, even in quiet, adults with dementia symptoms correctly identified words only about 80% of the time. However, word difficulty was not a factor in task performance for either group. Conclusion: These results affirm the difficulty that listeners with mild dementia may have with spoken word recognition, both in quiet and in background noise, consistent with a role of cognitive resources in spoken word identification. Show more

Keywords: Cognition, dementia, hearing, speech intelligibility, word processing

DOI: 10.3233/JAD-215606

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 749-759, 2022

Authors: Aerqin, Qiaolifan | Jia, Sha-Sha | Shen, Xue-Ning | Li, Quan | Chen, Ke-Liang | Ou, Ya-Nan | Huang, Yu-Yuan | Dong, Qiang | Chen, Shu-Fen | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Excessive oxidative stress may contribute to neurodegeneration by leading to protein aggregation and mitochondrial dysfunction. Uric acid (UA) is an important endogenous antioxidant that protects against oxidative stress, yet its exact role in neurodegeneration remains unclear. Objective: To explore the performance of serum UA in neurodegenerative disorders. Methods: A total of 839 controls and 840 patients, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), motor neuron disease (MND), Creutzfeldt-Jakob disease (CJD), and mixed dementia (MixD) were enrolled. Fasting serum UA …levels were measured in all participants and compared between patients and controls. Linear regression models were utilized to explore possible relationships of serum UA with cognition, disease duration, age, and age of onset. Results: Compared to controls (355.48 ± 85.38 μmol/L), serum UA was significantly lower in AD (291.29 ± 83.49 μmol/L, p  < 0.001), PD (286.95 ± 81.78 μmol/L, p  < 0.001), PSP (313.32 ± 88.19 μmol/L, p  < 0.001), FTD (313.89 ± 71.18 μmol/L, p  = 0.001), and DLB (279.23 ± 65.51 μmol/L, p  < 0.001), adjusting for confounding factors including age, gender, education, etc. In addition, serum UA was positively correlated with cognitive levels in all patients (Mini-Mental State Examination: r = 0.136, p  = 0.001; and Montreal Cognitive Assessment Scale: r = 0.108, p  = 0.009). Conclusion: Decreased levels of serum UA were correlated with AD, PD, PSP, FTD, and DLB, offering significant potential as a promisingly relevant, less-invasive marker of multiple neurodegenerative disorders. Show more

Keywords: Cognition, neurodegeneration, oxidative stress, uric acid

DOI: 10.3233/JAD-220432

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 761-773, 2022

Authors: Shepherd-Banigan, Megan E. | Ford, Cassie B. | Smith, Valerie A. | Belanger, Emmanuelle | Wetle, Terrie T. | Plassman, Brenda L. | Burke, James R. | DePasquale, Nicole | O’Brien, Emily C. | Sorenson, Corinna | Van Houtven, Courtney H.

Article Type: Research Article

Abstract: Background: Diagnostic tests, such as amyloid-β positron emission tomography (PET) scans, can increase appropriate therapeutic management for the underlying causes of cognitive decline. To evaluate the full utility of this diagnostic tool, information is needed on whether results from amyloid-β PET scans influence care-partner outcomes. Objective: This study examines the extent to which previous disclosure of elevated amyloid (suggestive of Alzheimer’s disease (AD) etiology) versus not-elevated amyloid (not suggestive of AD etiology) is associated with changes in care-partner wellbeing. Methods: The study used data derived from a national longitudinal survey of Medicare beneficiaries (n  = 921) with …mild cognitive impairment (MCI) or dementia and their care-partners. Care-partner wellbeing outcomes included depressive symptoms (PHQ-8), subjective burden (4-item Zarit burden score), and a 3-item measure of loneliness. Change was measured between 4 (Time 1) and 18 (Time 2) months after receiving the scan results. Adjusted linear regression models regressed change (Time 2-Time 1) in each outcome on scan result. Results: Care-partners were primarily white, non-Hispanic, college-educated, and married to the care recipient. Elevated amyloid was not associated with statistically significant Time 1 differences in outcomes or with statistically significant changes in depressive symptoms 0.22 (–0.18, 0.61), subjective burden 0.36 (–0.01, 0.73), or loneliness 0.15 (–0.01, 0.32) for care-partners from one time point to another. Conclusion: Given advances in AD biomarker testing, future research in more diverse samples is needed to understand the influence of scan results on care-partner wellbeing across populations. Show more

Keywords: Amyloid-β, caregiver, dementia, depression, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-220611

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 775-782, 2022

Authors: Lin, Junhan | Yang, Siyu | Wang, Chao | Yu, Erhan | Zhu, Zhibao | Shi, Jinying | Li, Xiang | Xin, Jiawei | Chen, Xiaochun | Pan, Xiaodong

Article Type: Research Article

Abstract: Background: DNA methylation is expected to become a kind of new diagnosis and treatment method of Alzheimer’s disease (AD). Neuroinflammation- and immune-related pathways represent one of the major genetic risk factors for AD. Objective: We aimed to investigate DNA methylation levels of 7 key immunologic-related genes in peripheral blood and appraise their applicability in the diagnosis of AD. Methods: Methylation levels were obtained from 222 participants (101 AD, 72 MCI, 49 non-cognitively impaired controls). Logistic regression models for diagnosing AD were established after least absolute shrinkage and selection operator (LASSO) and best subset selection (BSS), evaluated …by respondent working curve and decision curve analysis for sensitivity. Results: Six differentially methylated positions (DMPs) in the MCI group and 64 in the AD group were found, respectively. Among them, there were 2 DMPs in the MCI group and 30 DMPs in the AD group independent of age, gender, and APOE4 carriers (p  <  0.05). AD diagnostic prediction models differentiated AD from normal controls both in a training dataset (LASSO: 8 markers, including methylation levels at ABCA7 1040077 , CNR1 88166293 , CX3CR1 39322324 , LRRK2 40618505 , LRRK2 40618493 , NGFR 49496745 , TARDBP 11070956 , TARDBP 11070840 area under the curve [AUC] = 0.81; BSS: 2 markers, including methylation levels at ABCA7 1040077 and CX3CR1 39322324 , AUC = 0.80) and a testing dataset (AUC = 0.84, AUC = 0.82, respectively). Conclusion: Our work indicated that methylation levels of 7 key immunologic-related genes (ABCA7 , CNR1 , CX3CR1 , CSF1R , LRRK2 , NGFR , and TARDBP ) in peripheral blood was altered in AD and the models including methylation of immunologic-related genes biomarkers improved prediction of AD. Show more

Keywords: Alzheimer’s disease, clinical prediction model, immunologic-related genes, methylation, mild cognitive impairment

DOI: 10.3233/JAD-220701

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 783-794, 2022

Authors: Guo, Qian | Cai, Qinfeng | Huang, Fang | Wei, Zhen | Wang, Jian-Zhi | Zhang, Bin | Liu, Rong | Yang, Yang | Wang, Xiaochuan | Li, Hong-Lian

Article Type: Research Article

Abstract: Background: As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer’s disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycopodium alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. Objective: To systematically evaluate the therapeutic effects of the seven compounds on AD cell models. Methods: We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to …evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. Results: All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3β-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAβPPα level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAβPPβ, thereby reduced Aβ production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10μM. Conclusion: Among the seven Lycopodium compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Aβ production and inhibiting AChE in AD. Show more

Keywords: Alzheimer’s disease, beta-Secretase 1, cholinesterase inhibitor, Lycopodium alkaloid, protein phosphatase-2A

DOI: 10.3233/JAD-220704

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 795-809, 2022

Authors: Blivet, Guillaume | Relano-Gines, Aroa | Wachtel, Mélanie | Touchon, Jacques

Article Type: Research Article

Abstract: Background: Recent innovative non-pharmacological interventions and neurostimulation devices have shown potential for application in the treatment of Alzheimer’s disease (AD). These include photobiomodulation (PBM) therapy. Objective: This pilot study assesses the safety, compliance with, and efficacy of a brain-gut PBM therapy for mild-to-moderate AD patients. Methods: This double-blind, randomized, monocentric sham-controlled study started in 2018 and ended prematurely in 2020 due to the COVID-19 pandemic. Fifty-three mild-to-moderate AD patients were randomized, 27 in the PBM group and 26 in the sham group. All patients had 40 treatment sessions lasting 25 min each over 8 weeks and were …followed for 4 weeks afterwards. Compliance with the treatment was recorded. Safety was assessed by recording adverse events (AEs), and efficacy was evaluated using neuropsychological tests. Results: The PBM therapy proved to be safe in regard to the number of recorded AEs (44% of the patients), which were balanced between the PBM and sham groups. AEs were mainly mild, and no serious AEs were reported. The majority of the patients (92.5%) were highly compliant, which confirms the feasibility of the PBM treatment. Compared to the sham patients, the PBM patients showed lower ADAS-Cog comprehension subscores, higher forward verbal spans, and lower TMT-B execution times, which suggests an improvement in cognitive functions. Conclusion: This study demonstrates the tolerability of and patient compliance with a PBM-based treatment for mild-to-moderate AD patients. It highlights encouraging efficacy trends and provides insights for the design of the next phase trial in a larger AD patient sample. Show more

Keywords: Alzheimer’s disease, brain-gut axis, cognition, dementia, memory, neurodegenerative diseases, optics and photonics, photobiomodulation

DOI: 10.3233/JAD-220467

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 811-822, 2022

Authors: Valles-Salgado, María | Cabrera-Martín, María Nieves | Curiel-Cid, Rosie E. | Delgado-Álvarez, Alfonso | Delgado-Alonso, Cristina | Gil-Moreno, María José | Matías-Guiu, Jorge | Loewenstein, David A. | Matias-Guiu, Jordi A.

Article Type: Research Article

Abstract: Background: LASSI-L is a novel neuropsychological test specifically designed for the early diagnosis of Alzheimer’s disease (AD) based on semantic interference. Objective: To examine the cognitive and neural underpinnings of the failure to recover from proactive semantic and retroactive semantic interference. Methods: One hundred and fifty-five patients consulting for memory loss were included. Patients underwent neuropsychological assessment, including the LASSI-L, and FDG-PET imaging. They were categorized as subjective memory complaints (SMC) (n=32), pre-mild cognitive impairment (MCI) due to AD (Pre-MCI) (n=39), MCI due to AD (MCI-AD) (n=71), and MCI without evidence of neurodegeneration (MCI-NN) (n=13). Voxel-based …brain mapping and metabolic network connectivity analyses were conducted. Results: A significant group effect was found for all the LASSI-L scores. LASSI-L scores measuring failure to recover from proactive semantic interference and retroactive semantic interference were predicted by other neuropsychological tests with a precision of 64.1 and 44.8%. The LASSI-L scores were associated with brain metabolism in the bilateral precuneus, superior, middle and inferior temporal gyri, fusiform, angular, superior and inferior parietal lobule, superior, middle and inferior occipital gyri, lingual gyrus, and posterior cingulate. Connectivity analysis revealed a decrease of node degree and centrality in posterior cingulate in patients showing frPSI. Conclusion: Episodic memory dysfunction and the involvement of the medial temporal lobe, precuneus and posterior cingulate constitute the basis of the failure to recover from proactive semantic interference and retroactive semantic interference. These findings support the role of the LASSI-L in the detection, monitoring and outcome prediction during the early stages of AD. Show more

Keywords: Alzheimer’s disease, connectivity, FDG-PET, interference, memory, mild cognitive impairment, neuropsychological assessment

DOI: 10.3233/JAD-220754

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 823-840, 2022

Authors: Shen, Wei-Bin | Elahi, Montasir | Wang, Bingbing | Zhan, Min | Yang, Penghua | Yang, Peixin

Article Type: Research Article

Abstract: Background: The cascade of events that lead to Alzheimer’s disease (AD) consists of several possible underlying signal transduction pathways. Apoptosis signal-regulating kinase 1 (ASK1) and insulin receptor (IR) signaling are implicated in AD. Objective: We aimed to determine whether ASK1 activation and IR signaling impairment occurred prior to and during overt AD. Methods: Immunostaining, immunoblotting, and quantitative PCR were used to assess the levels of ASK1 and IR signaling intermediates. Glucose uptake was determined in AD-patient derived inducible pluripotent stem cells (iPSCs). Results: ASK1 signaling was activated in postmortem brain tissues acquired from APOE4 …carriers, a causative heritable factor, and in brain tissues of AD subjects in comparison with those harboring the normal APOE3 variant, which was manifested with an increased phosphorylated ASK1 (p-ASK1) and reduced thioredoxin 1 (TRX1). ASK1 downstream signaling effectors were also significantly elevated in these APOE4 carriers and AD brain tissues. Increased insulin receptor substrate 1 (IRS1) phosphorylation at serine residues, and decreased p-AKT1, p-IRβ, and GLUT3 expression were present in all APOE4 carriers and AD samples, suggesting impaired IR signaling leading to insulin resistance. ASK1 activation, IR signaling impairment, and GLUT3 reduction were also present in young AD transgenic mice prior to AD syndromes, AD mice at AD neuropathology onset, and AD iPSCs and their derived neurons prior to p-Tau aggregation. Conclusion: We conclude that the activation of oxidative stress-responsive kinases and reduced IR signaling precede and are persistent in AD pathogenesis. Our data further suggest possible crosstalk between ASK1 signaling and insulin resistance in AD etiology. Show more

Keywords: Alzheimer’s disease, ASK1 signaling, GLUT3, insulin resistance, metabolic dysregulation, neuropathology, oxidative stress

DOI: 10.3233/JAD-215687

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 841-857, 2022