Journal of Alzheimer's Disease - Volume 97, issue 1

Authors: Possemis, Nina | ter Huurne, Daphne | Banning, Leonie | Gruters, Angelique | Van Asbroeck, Stephanie | König, Alexandra | Linz, Nicklas | Tröger, Johannes | Langel, Kai | Blokland, Arjan | Prickaerts, Jos | de Vugt, Marjolein | Verhey, Frans | Ramakers, Inez

Article Type: Research Article

Abstract: Background: Previous research has shown that verbal memory accurately measures cognitive decline in the early phases of neurocognitive impairment. Automatic speech recognition from the verbal learning task (VLT) can potentially be used to differentiate between people with and without cognitive impairment. Objective: Investigate whether automatic speech recognition (ASR) of the VLT is reliable and able to differentiate between subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Methods: The VLT was recorded and processed via a mobile application. Following, verbal memory features were automatically extracted. The diagnostic performance of the automatically derived features was investigated by …training machine learning classifiers to distinguish between participants with SCD versus MCI/dementia. Results: The ICC for inter-rater reliability between the clinical and automatically derived features was 0.87 for the total immediate recall and 0.94 for the delayed recall. The full model including the total immediate recall, delayed recall, recognition count, and the novel verbal memory features had an AUC of 0.79 for distinguishing between participants with SCD versus MCI/dementia. The ten best differentiating VLT features correlated low to moderate with other cognitive tests such as logical memory tasks, semantic verbal fluency, and executive functioning. Conclusions: The VLT with automatically derived verbal memory features showed in general high agreement with the clinical scoring and distinguished well between SCD and MCI/dementia participants. This might be of added value in screening for cognitive impairment. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, memory, speech

DOI: 10.3233/JAD-230608

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 179-191, 2024

Authors: Na, Seunghee | Lee, Chonghwee | Ho, SeongHee | Hong, Yun Jeong | Jeong, Jee Hyang | Park, Kee Hyung | Kim, SangYun | Wang, Min Jeong | Choi, Seong Hye | Han, SeungHyun | Kang, Seung Wan | Kang, Sungmin | Yang, Dong Won

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) refers to the self-reported persistent cognitive decline despite normal objective testing, increasing the risk of dementia compared to cognitively normal individuals. Objective: This study aims to investigate the attributes of SCD patients who demonstrated memory function improvement. Methods: In this prospective study of SCD, a total of 120 subjects were enrolled as part of a multicenter cohort study aimed at identifying predictors for the clinical progression to mild cognitive impairment or dementia (CoSCo study). All subjects underwent 18 F-florbetaben PET and brain MRI scans at baseline and annual neuropsychological tests. At …the 24-month follow-up, we classified SCD patients based on changes in memory function, the z-score of the Seoul verbal learning test delayed recall. Results: Of the 120 enrolled patients, 107 successfully completed the 24-month follow-up assessment. Among these, 80 patients (74.8%) with SCD exhibited memory function improvements. SCD patients with improved memory function had a lower prevalence of coronary artery disease at baseline and performed better in the trail-making test part B compared to those without improvement. Anatomical and biomarker analysis showed a lower frequency of amyloid PET positivity and larger volumes in the left and right superior parietal lobes in subjects with improved memory function. Conclusions: Our prospective study indicates that SCD patients experiencing memory improvement over a 24-month period had a lower amyloid burden, fewer cardiovascular risk factors, and superior executive cognitive function. Identifying these key factors associated with cognitive improvement may assist clinicians in predicting future memory function improvements in SCD patients. Show more

Keywords: Alzheimer’s disease, cohort study, improvement, memory, subject cognitive decline

DOI: 10.3233/JAD-230667

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 193-204, 2024

Authors: Chunchai, Titikorn | Apaijai, Nattayaporn | Janjek, Sornram | Arunsak, Busarin | Nipon, Chattipakorn | Chattipakorn, Siriporn C.

Article Type: Research Article

Abstract: Background: Cardiac ischemia/reperfusion (I/R) injury has been shown to impose deleterious effects not only on the heart but also on the brain. Our previous study demonstrated that pretreatment with a mitochondrial fusion promoter (M1) provided central neuroprotective effects following cardiac I/R injury. Objective: To investigate the effects of M1 given during the ischemic phase and M1 given at the beginning of reperfusion on brain pathologies following cardiac I/R. Methods: Male Wistar rats were randomly divided into either a sham operation (n  = 6) or cardiac I/R injury (n  = 18) group. Rats with cardiac I/R injury were then …randomly divided into 3 subgroups: 1) Control, 2) M1 treatment during cardiac ischemia (2 mg/kg, intravenous (i.v.)), and 3) M1 treatment at the beginning of reperfusion (2 mg/kg, i.v.). After euthanasia, the brain of each rat was removed for further analysis. Results: Cardiac I/R injury caused brain mitochondrial dynamic imbalance, brain mitochondrial dysfunction, brain apoptosis, microglial dysmorphology, brain inflammation, tau hyperphosphorylation, and synaptic dysplasticity. M1 treatment at both time points effectively improved these parameters. M1 given during the ischemic phase had greater efficacy with regard to preventing brain mitochondrial dysfunction and suppressing brain inflammation, when compared to M1 given at the beginning of reperfusion. Conclusions: Our findings suggest that treatment with this mitochondrial fusion promoter prevents mitochondrial dynamic imbalance in the brain of rats with cardiac I/R injury, thereby attenuating brain pathologies. Interestingly, giving the mitochondrial fusion promoter during the ischemic phase exerted greater neuroprotection than if given at the beginning of reperfusion. Show more

Keywords: Alzheimer’s disease, brain, ischemic/reperfusion injury, microglia, mitochondrial function, mitochondrial fusion promoter

DOI: 10.3233/JAD-230859

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 205-217, 2024

Authors: Alshaheri Durazo, Alin | Weigand, Alexandra J. | Bangen, Katherine J. | Membreno, Rachel | Mudaliar, Sunder | Thomas, Kelsey R.

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) affects ∼25% of Veterans, a prevalence rate double that of the general population. T2DM is associated with greater dementia risk and has been shown to exacerbate the impact of Alzheimer’s disease (AD) risk factors on declines in daily functioning; however, there are few studies that investigate these patterns in older Veterans. Objective: This study sought to determine whether T2DM moderates the association between amyloid-β (Aβ) positron emission tomography (PET) and 1-year change in everyday functioning in older Veterans. Methods: One-hundred-ninety-eight predominately male Vietnam-Era Veterans without dementia from …the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI) with (n  = 74) and without (n  = 124) T2DM completed Aβ PET imaging and everyday functioning measures, including the Clinical Dementia Rating–Sum of Boxes (CDR-SB) and Everyday Cognition (ECog). Linear mixed effects models tested the moderating role of T2DM on the association between Aβ PET and 1-year change in everyday functioning. Results: The 3-way T2DM×Aβ PET×time interaction was significant for CDR-SB (p  < 0.001) as well as the Memory (p  = 0.007) and Language (p  = 0.011) subscales from the ECog. Greater amyloid burden was associated with greater increases in functional difficulties, but only in Veterans with T2DM. Conclusions: Higher Aβ was only associated with declines in everyday functioning over 1 year in Veterans with T2DM. Given that people with T2DM are more likely to have co-occurring cerebrovascular disease, the combination of multiple neuropathologies may result in faster declines. Future studies should examine how diabetes duration, severity, and medications impact these associations. Show more

Keywords: Alzheimer’s disease, amyloid PET, everyday functioning, type 2 diabetes, Veterans

DOI: 10.3233/JAD-230917

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 219-228, 2024

Authors: Zeng, Youjie | Cao, Si | Pang, Ke | Tang, Juan | Lin, Guoxin

Article Type: Research Article

Abstract: Background: Previous observational studies suggested an association between sepsis and neurodegenerative diseases, but causality remains unclear. Objective: Determining the causal association between sepsis and four neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Lewy body dementia) through bidirectional two-sample Mendelian randomization (MR) analysis. Methods: Genome-wide association study summary statistics for all traits were obtained from publicly available databases. Inverse variance weighted (IVW) was the primary method for evaluating causal associations. In addition, three additional MR methods (MR-Egger, weighted median, and maximum likelihood method) were employed to supplement IVW. Furthermore, various sensitivity tests were conducted …to assess the reliability: 1) Cochrane’s Q test for assessing heterogeneity; 2) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; 3) leave-one-out sensitivity test for determining the stability. Results: The results of IVW indicated that sepsis significantly increased the risk of Alzheimer’s disease (OR = 1.11, 95% CI: 1.01–1.21, p  = 0.025). In addition, three additional MR methods suggested parallel results. However, no causal effect of sepsis on the three other neurodegenerative diseases was identified. Subsequently, reverse MR analysis indicated that the four neurodegenerative diseases do not causally affect sepsis. Furthermore, sensitivity tests demonstrated the reliability of the MR analyses, suggesting no heterogeneity or horizontal pleiotropy. Conclusions: The present study contributes to a deeper comprehension of the intricate interplay between sepsis and neurodegenerative disorders, thereby offering potential avenues for the development of therapeutic agents that can effectively mitigate the multifarious complications associated with sepsis. Show more

Keywords: Alzheimer’s disease, causal relationship, incidence risk, Mendelian randomization, neurodegenerative disorders, risk factors, septic infection

DOI: 10.3233/JAD-230954

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 229-237, 2024

Authors: Schmued, Larry | Maloney, Bryan | Schmued, Calvert | Lahiri, Debomoy K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most prevalent age-related dementia, and, despite numerous attempts to halt or reverse its devastating progression, no effective therapeutics have yet been confirmed clinically. However, one class of agents that has shown promise is certain metal chelators. Objective: For the novel assessment of the effect of oral administration of 1,10-phenanthroline-5-amine (PAA) on the severity of amyloid plaque load, we used a transgenic (Tg) mouse model with inserted human autosomally dominant (familial) AD genes: amyloid-β protein precursor (AβPP) and tau. Methods: AβPP/Tau transgenic mice that model AD were allotted into one of …two groups. The control group received no treatment while the experimental group received PAA in their drinking water starting at 4 months of age. All animals were sacrificed at 1 year of age and their brains were stained with two different markers of amyloid plaques, Amylo-Glo+ and HQ-O. Results: The control animals exhibited numerous dense core plaques throughout the neo- and allo- cortical brain regions. The experimental group treated with PAA, however, showed 62% of the amyloid plaque burden seen in the control group. Conclusions: Oral daily dosing with PAA will significantly reduce the amyloid plaque burden in transgenic mice that model AD. The underlying mechanism for this protection is not fully known; however, one proposed mechanism involves inhibiting the “metal-seeding” of Aβ. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, metal chelators, metalloproteinase, neurodegenerative disorders

DOI: 10.3233/JAD-221285

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 239-247, 2024

Authors: Jiang, Lujing | Hu, Xiangming | Jin, Junguo | Wang, Weimian | Yu, Bingyan | Chen, Guo | Dong, Haojian | Zhou, Yingling

Article Type: Research Article

Abstract: Background: The association between uric acid (UA) and cognitive function still remains controversial. Moreover, the role of inflammation in the above association is also unclear. Objective: We aimed to determine the association between UA and cognitive function among non-hyperuricemia adults, and in particular, whether the association was shaped by different inflammation levels. Methods: From the China Health and Retirement Longitudinal Study (CHARLS), 7,272 participants aged 45 and above were enrolled in 2011. Cognitive function measurement included orientation and attention, episodic memory, and visuospatial ability. Fasting blood samples were collected to measure levels of UA and high-sensitivity …C-reactive protein (hs-CRP). Generalized estimating equation models were used to evaluate the effect of UA on cognitive function in all participants and those at different levels of hs-CRP (hs-CRP <3 mg/L or ≥3 mg/L). Results: Among non-hyperuricemia adults (mean age: 58.08, 49.59% males) for a median of 7 years follow-up, participants with higher levels of UA had better cognitive function score compared to those with lower UA levels (β: 0.09, 95% confidence interval [CI]: 0.01–0.17, p  = 0.023). And this association was significant under low-grade inflammation levels condition (β:0.10, 95% CI: 0.10–0.19, p  = 0.024), but not in high-grade inflammation levels condition. Further, the cognitive function benefit of elevated UA existed only in people with persistent low-grade inflammation levels at a longitudinal perspective (β: 0.14, 95% CI: 0.01–0.27, p  = 0.039). Conclusions: Elevated UA levels were associated with better cognitive function in non-hyperuricemia population, especially for those at low inflammation levels. Show more

Keywords: Alzheimer’s disease, cognitive function, inflammation, non-hyperuricemia, uric acid

DOI: 10.3233/JAD-230841

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 249-257, 2024

Authors: Kim, Regina E.Y. | Lee, Minho | Kang, Dong Woo | Wang, Sheng-Min | Kim, Donghyeon | Lim, Hyun Kook

Article Type: Research Article

Abstract: Background: Brain volume is associated with cognitive decline in later life, and cortical brain atrophy exceeding the normal range is related to inferior cognitive and behavioral outcomes in later life. Objective: To investigate the likelihood of cognitive decline, mild cognitive impairment (MCI), or dementia, when regional atrophy is present in participants’ magnetic resonance imaging (MRI). Methods: Multi-center MRI data of 2,545 adults were utilized to measure regional volumes using NEUROPHET AQUA. Four lobes (frontal, parietal, temporal, and occipital), four Alzheimer’s disease-related regions (entorhinal, fusiform, inferior temporal, and middle temporal area), and the hippocampus in the left …and right hemispheres were measured and analyzed. The presence of regional atrophy from brain MRI was defined as ≤1.5 standard deviation (SD) compared to the age- and sex-matched cognitively normal population. The risk ratio for cognitive decline was investigated for participants with regional atrophy in contrast to those without regional atrophy. Results: The risk ratio for cognitive decline was significantly higher when hippocampal atrophy was present (MCI, 1.84, p  < 0.001; dementia, 4.17, p  < 0.001). Additionally, participants with joint atrophy in multiple regions showed a higher risk ratio for dementia, e.g., 9.6 risk ratio (95% confidence interval, 8.0–11.5), with atrophy identified in the frontal, temporal, and hippocampal gray matter, than those without atrophy. Conclusions: Our study showed that individuals with multiple regional atrophy (either lobar or AD-specific regions) have a higher likelihood of developing dementia compared to the age- and sex-matched population without atrophy. Thus, further consideration is needed when assessing MRI findings. Show more

Keywords: Alzheimer’s disease, atrophy, cognitive decline, dementia, mild cognitive impairment

DOI: 10.3233/JAD-230602

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 259-271, 2024

Authors: Park, Yu Shin | Joo, Hye Jin | Jang, Yun Seo | Jeon, Hajae | Park, Eun-Cheol | Shin, Jaeyong

Article Type: Research Article

Abstract: Background: In aging populations, more elderly patients are going to the intensive care unit (ICU) and surviving. However, the specific factors influencing the occurrence of post-intensive care syndrome in the elderly remain uncertain. Objective: To investigate the association between socioeconomic status (SES) and risk of developing dementia within two years following critical care. Methods: This study included participants from the Korean National Health Insurance Service Cohort Database who had not been diagnosed with dementia and had been hospitalized in the ICU from 2003 to 2019. Dementia was determined using specific diagnostic codes (G30, G31) and prescription …of certain medications (rivastigmine, galantamine, memantine, or donepezil). SES was categorized into low (medical aid beneficiaries) and non-low (National Health Insurance) groups. Through a 1:3 propensity score matching based on sex, age, Charlson comorbidity index, and primary diagnosis, the study included 16,780 patients. We used Cox proportional hazard models to estimate adjusted hazard ratios (HR) of dementia. Results: Patients with low SES were higher risk of developing dementia within 2 years after receiving critical care than those who were in non-low SES (HR: 1.23, 95% CI: 1.04–1.46). Specifically, patients with low SES and those in the high-income group exhibited the highest incidence rates of developing dementia within two years after receiving critical care, with rates of 3.61 (95% CI: 3.13–4.17) for low SES and 2.58 (95% CI: 2.20–3.03) for high income, respectively. Conclusions: After discharge from critical care, compared to the non-low SES group, the low SES group was associated with an increased risk of developing dementia. Show more

Keywords: Alzheimer’s disease, critical care, dementia, disparity, post intensive care syndrome, socioeconomic status

DOI: 10.3233/JAD-230715

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 273-281, 2024

Authors: Morris, Jill K. | Kueck, Paul J. | Kemna, Riley E. | Green, Zachary D. | John, Casey S. | Winter, Michelle | Billinger, Sandra A. | Vidoni, Eric D.

Article Type: Research Article

Abstract: Background: There is evidence that aerobic exercise is beneficial for brain health, but these effects are variable between individuals and the underlying mechanisms that modulate these benefits remain unclear. Objective: We sought to characterize the acute physiological response of bioenergetic and neurotrophic blood biomarkers to exercise in cognitively healthy older adults, as well as relationships with brain blood flow. Methods: We measured exercise-induced changes in lactate, which has been linked to brain blood flow, as well brain-derived neurotrophic factor (BDNF), a neurotrophin related to brain health. We further quantified changes in brain blood flow using arterial …spin labeling. Results: As expected, lactate and BDNF both changed with time post exercise. Intriguingly, there was a negative relationship between lactate response (area under the curve) and brain blood flow measured acutely following exercise. Finally, the BDNF response tracked strongly with change in platelet activation, providing evidence that platelet activation is an important mechanism for trophic-related exercise responses. Conclusions: Lactate and BDNF respond acutely to exercise, and the lactate response tracks with changes in brain blood flow. Further investigation into how these factors relate to brain health-related outcomes in exercise trials is warranted. Show more

Keywords: Aging, Alzheimer’s disease, brain-blood flow, brain-derived neurotrophic factor, exercise, growth factor, lactate

DOI: 10.3233/JAD-230766

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 283-292, 2024