Journal of Alzheimer's Disease - Volume 96, issue 3

Authors: Wu, Wenzhe | Shen, Audrey | Lee, Inhan | Miranda-Morales, Ernesto G. | Spratt, Heidi | Pappolla, Miguel A. | Fang, Xiang | Bao, Xiaoyong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia, affecting individuals over 65. AD is also a multifactorial disease, with disease mechanisms incompletely characterized, and disease-modifying therapies are marginally effective. Biomarker signatures may shed light on the diagnosis, disease mechanisms, and the development of therapeutic targets. tRNA-derived RNA fragments (tRFs), a family of recently discovered small non-coding RNAs, have been found to be significantly enhanced in human AD hippocampus tissues. However, whether tRFs change in body fluids is unknown. Objective: To investigate whether tRFs in body fluids are impacted by AD. Methods: We first …used T4 polynucleotide kinase-RNA-seq, a modified next-generation sequencing technique, to identify detectable tRFs in human cerebrospinal fluid and serum samples. The detectable tRFs were then compared in these fluids from control, AD, and mild cognitive impairment patients using tRF qRT-PCR. The stability of tRFs in serum was also investigated by checking the change in tRFs in response to protein digestion or exosome lysis. Results: Among various tRFs, tRF5-ProAGG seemed to be impacted by AD in both cerebrospinal fluid and serum. AD-impacted serum tRF5-ProAGG showed a correlation with the AD stage. Putative targets of tRF5-ProAGG in the hippocampus were also predicted by a computational algorithm, with some targets being validated experimentally and one of them being in a negative correlation with tRF5-ProAGG even using a small size of samples. Conclusions: tRF5-ProAGG showed the potential as an AD biomarker and may play a role in disease progression. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, serum, tRNA-derived RNA fragments

DOI: 10.3233/JAD-230412

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1285-1304, 2023

Authors: Perron, Jarrad | Scramstad, Carly | Ko, Ji Hyun

Article Type: Research Article

Abstract: Background: The approval of lecanemab for the treatment of Alzheimer’s disease (AD) by the Food and Drug Administration in the United States has sparked controversy over issues of safety, cost, and efficacy. Furthermore, the prognostication of cognitive decline is prohibitively difficult with current methods. The inability to forecast incipient dementia in patients with biological AD suggests a prophylactic scenario wherein all patients with cognitive decline are prescribed anti-AD drugs at the earliest manifestations of dementia; however, most patients with mild cognitive impairment (approximately 77.7%) do not develop dementia over a 3-year period. Prophylactic response therefore constitutes unethical, costly, and unnecessary …treatment for these patients. Objective: We present a snapshot of the costs associated with the first 3 years of mass availability of anti-AD drugs in a variety of scenarios. Methods: We consider multiple prognostication scenarios with varying sensitivities and specificities based on neuroimaging studies in patients with mild cognitive impairment to determine approximate costs for the large-scale use of lecanemab. Results: The combination of fluorodeoxyglucose and magnetic resonance was determined to be the most cost-efficient at $177,000 for every positive outcome every 3 years under an assumed adjustment in the price of lecanemab to $9,275 per year. Conclusions: Imaging-assisted identification of cognitive status in patients with prodromal AD is demonstrated to reduce costs and prevent instances of unnecessary treatment in all cases considered. This highlights the potential of this technology for the ethical prescription of anti-AD medications under a paradigm of imaging-assisted early detection for pharmaceutical intervention in the treatment of AD. Show more

Keywords: Alzheimer’s disease, biomarker, deep learning, dementia, mild cognitive impairment, pharmaceutical

DOI: 10.3233/JAD-230633

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1305-1315, 2023

Authors: Michopoulou, Sofia | Prosser, Angus | Dickson, John | Guy, Matthew | Teeling, Jessica L. | Kipps, Christopher

Article Type: Research Article

Abstract: Background: Single photon emission tomography (SPECT) can detect early changes in brain perfusion to support the diagnosis of dementia. Inflammation is a driver for dementia progression and measures of inflammation may further support dementia diagnosis. Objective: In this study, we assessed whether combining imaging with markers of inflammation improves prediction of the likelihood of Alzheimer’s disease (AD). Methods: We analyzed 91 participants datasets (Institutional Ethics Approval 20/NW/0222). AD biomarkers and markers of inflammation were measured in cerebrospinal fluid. Statistical parametric mapping was used to quantify brain perfusion differences in perfusion SPECT images. Logistic regression models were …trained to evaluate the ability of imaging and inflammation markers, both individually and combined, to predict AD. Results: Regional perfusion reduction in the precuneus and medial temporal regions predicted Aβ42 status. Increase in inflammation markers predicted tau and neurodegeneration. Matrix metalloproteneinase-10, a marker of blood-brain barrier regulation, was associated with perfusion reduction in the right temporal lobe. Adenosine deaminase, an enzyme involved in sleep homeostasis and inflammation, was the strongest predictor of neurodegeneration with an odds ratio of 10.3. The area under the receiver operator characteristic curve for the logistic regression model was 0.76 for imaging and 0.76 for inflammation. Combining inflammation and imaging markers yielded an area under the curve of 0.85. Conclusions: Study results showed that markers of brain perfusion imaging and markers of inflammation provide complementary information in AD evaluation. Inflammation markers better predict tau status while perfusion imaging measures represent amyloid status. Combining imaging and inflammation improves AD prediction. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, inflammation, perfusion, SPECT

DOI: 10.3233/JAD-230726

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1317-1327, 2023

Authors: Tu, Min-Chien | Chung, Hsiao-Wen | Hsu, Yen-Hsuan | Yang, Jir-Jei | Wu, Wen-Chau

Article Type: Research Article

Abstract: Background: Cobalamin (Cbl) and folate are common supplements clinicians prescribe as an adjuvant therapy for dementia patients, on the presumption of their neurotrophic and/or homocysteine (Hcy) lowering effect. However, the treatment efficacy has been found mixed and the effects of Cbl/folate/Hcy on the human brain remain to be elucidated. Objective: To explore the neurovascular correlates of Cbl/folate/Hcy in Alzheimer’s disease (AD) and subcortical ischemic vascular dementia (SIVD). Methods: Sixty-seven AD patients and 57 SIVD patients were prospectively and consecutively recruited from an outpatient clinic. Multimodal 3-Tesla magnetic resonance imaging was performed to quantitatively evaluate cerebral blood …flow (CBF) and white matter integrity. The relationship between neuroimaging metrics and the serum levels of Cbl/folate/Hcy was examined by using the Kruskal-Wallis test, partial correlation analysis, and moderation analysis, at a significance level of 0.05. Results: As a whole, CBF mainly associated with Cbl/folate while white matter hyperintensities exclusively associated with Hcy. As compared with AD, SIVD exhibited more noticeable CBF correlates (spatially widespread with Cbl and focal with folate). In SIVD, a bilateral Cbl-moderated CBF coupling was found between medial prefrontal cortex and ipsilateral basal ganglia, while in the fronto-subcortical white matter tracts, elevated Hcy was associated with imaging metrics indicative of increased injury in both axon and myelin sheath. Conclusions: We identified the neurovascular correlates of previously reported neurotrophic effect of Cbl/folate and neurotoxic effect of Hcy in dementia. The correlates exhibited distinct patterns in AD and SIVD. The findings may help improving the formulation of supplemental Cbl/folate treatment for dementia. Show more

Keywords: Alzheimer’s disease, cerebral blood flow, cobalamin, homocysteine, magnetic resonance imaging, vascular dementia

DOI: 10.3233/JAD-230763

Citation: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1329-1338, 2023