Journal of Alzheimer's Disease - Volume 97, issue 3

Authors: Gurjar, Pankaj | Khan, Azmat Ali | Alanazi, Amer M. | Vasil’ev, Vasilii G. | Zouganelis, George | Alexiou, Athanasios

Article Type: Research Article

Abstract: Background: Herpes simplex virus type 1 (HSV-1) is associated with Alzheimer’s disease, which goes into a cycle of latency and reactivation. The present study was envisaged to understand the reasons for latency and specific molecular patterns present in the HSV-1. Objective: The objective is the molecular dissection of Herpes simplex virus type 1 to elucidate molecular mechanisms behind latency and compare its codon usage patterns with genes modulated during Alzheimer’s disease as a part of host-pathogen interaction. Methods: In the present study, we tried to investigate the potential reasons for the latency of HSV-1 virus bioinformatically …by determining the CpG patterns. Also, we investigated the codon usage pattern, the presence of rare codons, codon context, and protein properties. Results: The top 222 codon pairs graded based on their frequency in the HSV-1 genome revealed that with only one exception (CUG-UUU), all other codon pairs have codons ending with G/C. Considering it an extension of host-pathogen interaction, we compared HSV-1 codon usage with that of codon usage of genes modulated during Alzheimer’s disease, and we found that CGT and TTT are only two codons that exhibited similar codon usage patterns and other codons showed statistically highly significant different codon preferences. Dinucleotide CpG tends to mutate to TpG, suggesting the presence of mutational forces and the imperative role of CpG methylation in HSV-1 latency. Conclusions: Upon comparison of codon usage between HSV-1 and Alzheimer’s disease genes, no similarities in codon usage were found as a part of host-pathogen interaction. CpG methylation plays an imperative role in latency HSV-1. Show more

Keywords: Alzheimer’s disease, codon context, codon usage, Herpes simplex virus type 1, rare codon, virus latency

DOI: 10.3233/JAD-231083

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1111-1123, 2024

Authors: Zhang, Chunchao | Lei, Xiaolin | Ma, Wenhao | Long, Jinyi | Long, Shun | Chen, Xiang | Luo, Jun | Tao, Qian

Article Type: Research Article

Abstract: Background: Emotion and cognition are intercorrelated. Impaired emotion is common in populations with Alzheimer’s disease (AD) and mild cognitive impairment (MCI), showing promises as an early detection approach. Objective: We aim to develop a novel automatic classification tool based on emotion features and machine learning. Methods: Older adults aged 60 years or over were recruited among residents in the long-term care facilities and the community. Participants included healthy control participants with normal cognition (HC, n  = 26), patients with MCI (n  = 23), and patients with probable AD (n  = 30). Participants watched emotional film clips while multi-dimensional emotion …data were collected, including mental features of Self-Assessment Manikin (SAM), physiological features of electrodermal activity (EDA), and facial expressions. Emotional features of EDA and facial expression were abstracted by using continuous decomposition analysis and EomNet, respectively. Bidirectional long short-term memory (Bi-LSTM) was used to train classification model. Hybrid fusion was used, including early feature fusion and late decision fusion. Data from 79 participants were utilized into deep machine learning analysis and hybrid fusion method. Results: By combining multiple emotion features, the model’s performance of AUC value was highest in classification between HC and probable AD (AUC = 0.92), intermediate between MCI and probable AD (AUC = 0.88), and lowest between HC and MCI (AUC = 0.82). Conclusions: Our method demonstrated an excellent predictive power to differentiate HC/MCI/AD by fusion of multiple emotion features. The proposed model provides a cost-effective and automated method that can assist in detecting probable AD and MCI from normal aging. Show more

Keywords: Alzheimer’s disease, cognitive impairment, emotion, machine learning

DOI: 10.3233/JAD-230703

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1125-1137, 2024

Authors: Kurano, Makoto | Saito, Yuko | Yatomi, Yutaka

Article Type: Research Article

Abstract: Background: Disturbed metabolism has been proposed as being involved in the pathogenesis of Alzheimer’s disease (AD), and more evidence from human AD brains is required. Objective: In this study, we attempted to identify or confirm modulations in the levels of metabolites associated with AD in postmortem AD brains. Methods: We performed metabolomics analyses using a gas chromatography mass spectrometry system in postmortem brains of patients with confirmed AD, patients with CERAD score B, and control subjects. Results: Impaired phosphorylation of glucose and elevation of several tricarboxylic acid (TCA) metabolites, except citrate, were observed and …the degree of impaired phosphorylation and elevation in the levels of the TCA cycle metabolites were negatively and positively correlated, respectively, with the clinical phenotypes of AD. The levels of uronic acid pathway metabolites were modulated in AD and correlated positively with the amyloid-β content. The associations of nucleic acid synthesis and amino acid metabolites with AD depended on the kinds of metabolites; in particular, the contents of ribose 5-phosphate, serine and glycine were negatively correlated, while those of ureidosuccinic acid and indole-3-acetic acid were positively modulated in AD. Comprehensive statistical analyses suggested that alterations in the inositol pathway were most closely associated with AD. Conclusions: The present study revealed many novel associations between metabolites and AD, suggesting that some of these might serve as novel potential therapeutic targets for AD. Show more

Keywords: Alzheimer’s disease, amino acids, inositol phosphate, metabolomics, nucleic acid synthesis, postmortem brain, uronic acid pathway

DOI: 10.3233/JAD-230942

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1139-1159, 2024

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

Article Type: Research Article

Abstract: Background: Elevated amyloid-β (Aβ) on positron emission tomography (PET) scan is used to aid diagnosis of Alzheimer’s disease (AD), but many prior studies have focused on patients with a typical AD phenotype such as amnestic mild cognitive impairment (MCI). Little is known about whether elevated Aβ on PET scan predicts rate of cognitive and functional decline among those with MCI or dementia that is clinically less typical of early AD, thus leading to etiologic uncertainty. Objective: We aimed to investigate whether elevated Aβ on PET scan predicts cognitive and functional decline over an 18-month period in those with …MCI or dementia of uncertain etiology. Methods: In 1,028 individuals with MCI or dementia of uncertain etiology, we evaluated the association between elevated Aβ on PET scan and change on a telephone cognitive status measure administered to the participant and change in everyday function as reported by their care partner. Results: Individuals with either MCI or dementia and elevated Aβ (66.6% of the sample) showed greater cognitive decline compared to those without elevated Aβ on PET scan, whose cognition was relatively stable over 18 months. Those with either MCI or dementia and elevated Aβ were also reported to have greater functional decline compared to those without elevated Aβ, even though the latter group showed significant care partner-reported functional decline over time. Conclusions: Elevated Aβ on PET scan can be helpful in predicting rates of both cognitive and functional decline, even among cognitively impaired individuals with atypical presentations of AD. Show more

Keywords: Activities of daily living, Alzheimer’s disease, amyloid-β , cognitive decline, dementia, functional status, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-230950

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1161-1171, 2024

Authors: Alegret, Montserrat | García-Gutiérrez, Fernando | Muñoz, Nathalia | Espinosa, Ana | Ortega, Gemma | Lleonart, Núria | Rodríguez, Isabel | Rosende-Roca, Maitee | Pytel, Vanesa | Cantero-Fortiz, Yahveth | Rentz, Dorene M. | Marquié, Marta | Valero, Sergi | Ruiz, Agustín | Butler, Christopher | Boada, Mercè

Article Type: Research Article

Abstract: Background: The FACEmemory® online platform comprises a complex memory test and sociodemographic, medical, and family questions. This is the first study of a completely self-administered memory test with voice recognition, pre-tested in a memory clinic, sensitive to Alzheimer’s disease, using information and communication technologies, and offered freely worldwide. Objective: To investigate the demographic and clinical variables associated with the total FACEmemory score, and to identify distinct patterns of memory performance on FACEmemory. Methods: Data from the first 3,000 subjects who completed the FACEmemory test were analyzed. Descriptive analyses were applied to demographic, FACEmemory, and medical and …family variables; t -test and chi-square analyses were used to compare participants with preserved versus impaired performance on FACEmemory (cut-off = 32); multiple linear regression was used to identify variables that modulate FACEmemory performance; and machine learning techniques were applied to identify different memory patterns. Results: Participants had a mean age of 50.57 years and 13.65 years of schooling; 64.07% were women, and 82.10% reported memory complaints with worries. The group with impaired FACEmemory performance (20.40%) was older, had less schooling, and had a higher prevalence of hypertension, diabetes, dyslipidemia, and family history of neurodegenerative disease than the group with preserved performance. Age, schooling, sex, country, and completion of the medical and family history questionnaire were associated with the FACEmemory score. Finally, machine learning techniques identified four patterns of FACEmemory performance: normal, dysexecutive, storage, and completely impaired. Conclusions: FACEmemory is a promising tool for assessing memory in people with subjective memory complaints and for raising awareness about cognitive decline in the community. Show more

Keywords: Alzheimer’s disease, community, computerized assessment, early detection, memory, memory impairment, new technologies, patient engagement, subjective memory complaints

DOI: 10.3233/JAD-230983

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1173-1187, 2024

Authors: Tseng, Yun-Ting | Chang, Yu-Ling | Chiu, Yen-Shiang

Article Type: Research Article

Abstract: Background: Individuals with amnestic mild cognitive impairment (aMCI), especially for those with multidomain cognitive deficits, should be clinically examined for determining risk of developing Alzheimer’s disease. English-speakers with aMCI exhibit language impairments mostly at the lexical–semantic level. Given that the language processing of Mandarin Chinese is different from that of alphabetic languages, whether previous findings for English-speakers with aMCI can be generalized to Mandarin Chinese speakers with aMCI remains unclear. Objective: This study examined the multifaceted language functions of Mandarin Chinese speakers with aMCI and compared them with those without cognitive impairment by using a newly developed language …test battery. Methods: Twenty-three individuals with aMCI and 29 individuals without cognitive impairment were recruited. The new language test battery comprises five language domains (oral production, auditory and reading comprehension, reading aloud, repetition, and writing). Results: Compared with the controls, the individuals with aMCI exhibited poorer performance in the oral production and auditory and reading comprehension domains, especially on tests involving effortful lexical and semantic processing. Moreover, the aMCI group made more semantic naming errors compared with their counterparts and tended to experience difficulty in processing items belonging to the categories of living objects. Conclusions: The pattern identified in the present study is similar to that of English-speaking individuals with aMCI across multiple language domains. Incorporating language tests involving lexical and semantic processing into clinical practice is essential and can help identify early language dysfunction in Mandarin Chinese speakers with aMCI. Show more

Keywords: Alzheimer’s disease, language tests, Mandarin Chinese, mild cognitive impairment, neuropsychological tests

DOI: 10.3233/JAD-230871

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1189-1209, 2024

Authors: Chai, Yin-He | Han, Yi-Peng | Zhang, Jin-Yan | Zhou, Jian-Bo

Article Type: Research Article

Abstract: Background: Accumulating evidence has demonstrated that hyperglycemia is a possible risk factor for mild cognitive impairment or Alzheimer’s disease. Diabetic retinopathy (DR) has been identified as a risk factor for dementia in patients with diabetes. Objective: This study aimed to investigate the causal relationships between DR and brain structure, cognitive function, and dementia. Methods: We performed bidirectional two-sample Mendelian randomization for DR, brain structure, cognitive function, and dementia using the inverse-variance weighted method. Results: Inverse-variance weighted analysis showed the association of DR with vascular dementia (OR = 1.68, 95% CI: 1.01–2.82), and dementia was significantly associated …with the increased risk of non-proliferative DR (NPDR) (OR = 1.76, 95% CI: 1.04–2.98). Furthermore, better cognitive performance was significantly associated with a reduced risk of NPDR (OR = 0.85, 95% CI: 0.74–0.98). No association was observed between DR and brain structure. Conclusions: These findings suggest that the association of DR with vascular dementia. The reciprocal effect of cognitive performance and dementia on NPDR risk highlights the potential benefits of dementia prevention for reducing the burden of DR. Show more

Keywords: Alzheimer’s disease, cerebral cortex, cognitive function, dementia, diabetic retinopathy, Mendelian randomization, vascular dementia

DOI: 10.3233/JAD-231022

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1211-1221, 2024

Authors: Karayiannis, Christopher C. | Srikanth, Velandai | Beare, Richard | Mehta, Hemal | Gillies, Mark | Phan, Thanh G. | Xu, Zheng Yang | Chen, Christine | Moran, Chris

Article Type: Research Article

Abstract: Background: Type 2 diabetes (T2D) is associated with an increased risk of dementia and early features may become evident even in mid-life. Characterizing these early features comprehensively requires multiple measurement modalities and careful selection of participants with and without T2D. Objective: We conducted a cross-sectional multimodal imaging study of T2D-discordant twins in late mid-life to provide insights into underlying mechanisms. Methods: Measurements included computerized cognitive battery, brain MRI (including arterial spin labelling, diffusion tensor, resting state functional), fluorodeoxyglucose (FDG)-PET, and retinal optical coherence tomography. Results: There were 23 pairs, mean age 63.7 (±6.1) years. …In global analyses, T2D was associated with poorer attention (β= –0.45, p <0.001) and with reduced FDG uptake (β= –5.04, p  = 0.02), but not with cortical thickness (p  = 0.71), total brain volume (p  = 0.51), fractional anisotropy (p  = 0.15), mean diffusivity (p  = 0.34), or resting state activity (p  = 0.4). Higher FDG uptake was associated with better attention (β= 3.19, p  = 0.01) but not with other cognitive domains. In regional analyses, T2D was associated with lower accumbens volume (β= –44, p  = 0.0004) which was in turn associated with poorer attention. Conclusion: T2D-related brain dysfunction in mid-life manifests as attentional loss accompanied by evidence of subtle neurodegeneration and global reduction in cerebral metabolism, in the absence of overt cerebrovascular disease. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, multimodal imaging, twins, type 2 diabetes mellitus

DOI: 10.3233/JAD-230640

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1223-1233, 2024

Authors: Zawiślak-Fornagiel, Katarzyna | Ledwoń, Daniel | Bugdol, Monika | Grażyńska, Anna | Ślot, Maciej | Tabaka-Pradela, Justyna | Bieniek, Izabela | Siuda, Joanna

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is considered to be the borderline of cognitive changes associated with aging and very early dementia. Cognitive functions in MCI can improve, remain stable or progress to clinically probable AD. Quantitative electroencephalography (qEEG) can become a useful tool for using the analytical techniques to quantify EEG patterns indicating cognitive impairment. Objective: The aim of our study was to assess spectral and connectivity analysis of the EEG resting state activity in amnestic MCI (aMCI) patients in comparison with healthy control group (CogN). Methods: 30 aMCI patients and 23 CogN group, matched by …age and education, underwent equal neuropsychological assessment and EEG recording, according to the same protocol. Results: qEEG spectral analysis revealed decrease of global relative beta band power and increase of global relative theta and delta power in aMCI patients. Whereas, decreased coherence in centroparietal right area considered to be an early qEEG biomarker of functional disconnection of the brain network in aMCI patients. In conclusion, the demonstrated changes in qEEG, especially, the coherence patterns are specific biomarkers of cognitive impairment in aMCI. Conclusions: Therefore, qEEG measurements appears to be a useful tool that complements neuropsychological diagnostics, assessing the risk of progression and provides a basis for possible interventions designed to improve cognitive functions or even inhibit the progression of the disease. Show more

Keywords: Alzheimer’s disease, electroencephalography, mild cognitive impairment, neurocognitive disorders, spectrum analysis

DOI: 10.3233/JAD-230485

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1235-1247, 2024

Authors: Panzavolta, Andrea | Cerami, Chiara | Marcone, Alessandra | Zamboni, Michele | Iannaccone, Sandro | Dodich, Alessandra

Article Type: Research Article

Abstract: Background: Although social cognitive dysfunction is a major feature of the behavioral variant of frontotemporal dementia (bvFTD), quantitative measurement of social behavior changes is poorly available in clinical settings. Objective: The aim of the study is to evaluate diagnostic accuracy of social-emotional questionnaires in distinguishing bvFTD from healthy control (HC) subjects and Alzheimer’s disease (AD) patients. Methods: We enrolled 29 bvFTD, 24 AD, and 18 HC subjects matched for age, sex, and education. Two informant-based measures of socio-emotional sensitivity and empathy (i.e., revised Self-Monitoring Scale (rSMS) and Interpersonal Reactivity Index (IRI)) were administered. One-way ANOVA was …performed to compare groups, whereas Receiver Operating Characteristics (ROC) curve analysis tested questionnaire ability in distinguishing groups. A short version of IRI (sIRI) was obtained by excluding the non-contributing subscale (i.e., personal distress). Results: Compared to HC and AD, bvFTD showed significantly lower scores in rSMS and IRI scores, except for IRI personal distress subscale. The sIRI showed an excellent performance in early diagnosis (bvFTD versus HC = AUC 0.95). Both sIRI and rSMS showed good performance in distinguishing bvFTD from AD (AUC 0.83). Conclusions: ROC analyses support the usefulness of informant social questionnaires in memory clinics and their potential value in screening procedures for research eligibility in forthcoming trials. In the timely diagnosis of bvFTD patients, IRI and rSMS may supply crucial information for the early detection of signs and symptoms affecting social-emotional skills, which might otherwise be underrecognized. Show more

Keywords: Alzheimer’s disease, diagnostic accuracy, frontotemporal dementia, interpersonal reactivity index, revised self-monitoring scale, social cognition

DOI: 10.3233/JAD-230591

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1249-1260, 2024