Journal of Alzheimer's Disease - Volume 90, issue 4

Authors: Libard, Sylwia | Giedraitis, Vilmantas | Kilander, Lena | Ingelsson, Martin | Alafuzoff, Irina

Article Type: Research Article

Abstract: Background: There are more than 300 presenilin-1 (PSEN1 ) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed. Objective: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer’s disease (sAD). Methods: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations. Results: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, …although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations. Conclusion: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness. Show more

Keywords: Alpha-synuclein, amyloid-β, cross-seeding, hyperphosphorylated tau, neuroinflammation, PSEN1, TDP43

DOI: 10.3233/JAD-220655

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1601-1614, 2022

Authors: Chaudhary, Shefali | Zhornitsky, Simon | Chao, Herta H. | van Dyck, Christopher H. | Li, Chiang-Shan R.

Article Type: Research Article

Abstract: Background: Earlier studies have described the neural markers of apathy in Alzheimer’s disease (AD) and mild cognitive impairment (MCI), but few focused on the motivation circuits. Here, we targeted hypothalamus, a hub of the motivation circuit. Objective: To examine hypothalamic resting state functional connectivity (rsFC) in relation to apathy. Methods: We performed whole-brain regression of hypothalamic rsFC against Apathy Evaluation Scale (AES) total score and behavioral, cognitive, and emotional subscores in 29 patients with AD/MCI and 28 healthy controls (HC), controlling for age, sex, education, cognitive status, and depression. We evaluated the results at a corrected …threshold and employed path analyses to assess possible interaction between hypothalamic rsFCs, apathy and depression/memory. Finally, we re-examined the findings in a subsample of amyloid-β-verified AD. Results: AES total score correlated negatively with hypothalamic precuneus (PCu)/posterior cingulate cortex (PCC) and positively with left middle temporal gyrus (MTG) and supramarginal gyrus rsFCs. Behavioral subscore correlated negatively with hypothalamic PCu/PCC and positively with middle frontal gyrus rsFC. Cognitive subscore correlated positively with hypothalamic MTG rsFC. Emotional subscore correlated negatively with hypothalamic calcarine cortex rsFC. In path analyses, hypothalamic-PCu/PCC rsFC negatively modulated apathy and, in turn, depression. The model where hypothalamic MTG rsFC and memory independently modulated apathy also showed a good fit. The findings of diminished hypothalamic-PCu/PCC rsFC in relation to apathy and, in turn, depression were confirmed in amyloid-verified AD. Conclusion: The findings together support a role of altered hypothalamic connectivity in relation to apathy and depression, and modulation of apathy by memory dysfunction. Show more

Keywords: Alzheimer’s disease, apathy, depression, hypothalamus, memory, resting state functional connectivity

DOI: 10.3233/JAD-220708

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1615-1628, 2022

Authors: Kochan, Nicole A. | Heffernan, Megan | Valenzuela, Michael | Sachdev, Perminder S. | Lam, Ben C.P. | Fiatarone Singh, Maria | Anstey, Kaarin J. | Chau, Tiffany | Brodaty, Henry

Article Type: Research Article

Abstract: Background: Self-administered computerized neuropsychological assessments (CNAs) provide lower cost, more accessible alternatives to traditional in-person assessments but lack critical information on psychometrics and subjective experience of older adults in remote testing environments. Objective: We used an online brief battery of computerized tasks selected from the Cogstate Brief Battery (CBB) and Cambridge Brain Sciences (CBS) to 1) determine test-retest reliability in an unsupervised setting; 2) examine convergent validity with a comprehensive ‘gold standard’ paper-and-pencil neuropsychological test battery administered in-person; and 3) explore user-experience of remote computerized testing and individual tests. Methods: Fifty-two participants (mean age 65.8±5.7 years) …completed CBB and CBS tests on their own computer, unsupervised from home, on three occasions, and visited a research center for an in-person paper-and-pencil assessment. They also completed a user-experience questionnaire. Results: Test-retest reliabilities varied for individual measures (ICCs = 0.20 to 0.83). Global cognition composites showed excellent reliability (ICCs > 0.8 over 1-month follow-up). A strong relationship between a combination of CNA measures and paper-and-pencil battery was found (canonical correlation R  = 0.87, p  = 0.04). Most tests were rated as enjoyable with easy-to-understand instructions. Ratings of general experience with online testing were mostly favorable; few had difficulty concentrating (17%) or using the computer for tasks (10%), although over one-third experienced performance anxiety (38%). Conclusion: A combined brief online battery selected from two CNAs demonstrated robust psychometric standards for reliability (global composite), and convergent validity with a gold standard battery, and mostly good usability and acceptability in the remote testing environment. Show more

Keywords: Healthcare acceptability, mental status and dementia tests, neuropsychological tests, psychometrics

DOI: 10.3233/JAD-220665

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1629-1645, 2022

Authors: Gao, Fan | Zhang, Peng-Fei | Gao, Jing | Song, Jinghui | Chi, Song

Article Type: Research Article

Abstract: Background: CC-chemokine ligand 2 (CCL2), the key immunomodulatory chemokine for microglial activation, has been implicated in the pathogenesis of Alzheimer’s disease (AD). Whether the association of CCL2 single nucleotide polymorphisms (SNPs) and the risk of AD is still controversial. Objective: We aimed to investigate whether CCL2 rs4586 SNP is associated with the pathological changes and cognitive decline of AD. Methods: A total of 486 participants with longitudinal cerebrospinal fluid (CSF) amyloid-β (Aβ) and phospho-tau (P-tau) biomarkers, 18 F-Florbetapir and 18 F-flortaucipir-positron emission tomography (PET), and cognitive assessments from the Alzheimer’s disease Neuroimaging Initiative were …included in the study. The effects of CCL2 rs4586 SNP on the pathological changes and cognitive decline of AD were assessed with linear mixed-effects models and evaluated according to the Aβ-status so as to identify whether the effects were independent of Aβ status. Results: CCL2 rs4586-CC carriers exhibited a slower global Aβ-PET accumulation, particularly within stage I and stage II. However, they exhibited a faster accumulation of CSF P-tau and global tau-PET standard uptake value ratios, especially in Braak I and Braak III/IV and the inferior temporal gyrus. The congruent effects of CCL2 rs4586 on tau accumulation existed only in the Aβ–group, as is shown in global tau-PET and Braak I. However, CCL2 rs4586 was not associated with the cognitive decline. Conclusion: Our findings showed that the CCL2 rs4586-CC (versus TT/TC) genotype was associated with slower Aβ deposition and faster tau accumulation, and the latter of which was independent of Aβ status. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, amyloid-β, CCL2, tau

DOI: 10.3233/JAD-220716

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1647-1657, 2022

Authors: Ma, Yanzhen | Li, Weizu | Fan, Chang | Wang, Yongzhong | Jiang, Hui | Yang, Wenming

Article Type: Research Article

Abstract: Background: N4-acetylcytidine (ac4C), an important posttranscriptional modification, is involved in various disease processes. Long noncoding RNAs (lncRNAs) regulate gene expression mainly through epigenetic modification, transcription, and posttranscriptional modification. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloidosis of the brain. However, the role of lncRNA ac4C modification in AD remains unclear. Objective: In this study, we investigated the association between ac4C modification and AD, and the underlying mechanisms of ac4C modification in AD. Methods: The male 9-month-old APP/PS1 double transgenic mice, age- and sex-matched wild type (WT) mice were used in this study. Then, ac4C-RIP-seq …and RNA-seq were used to comprehensively analyze lncRNA ac4C modification in AD mice. The lncRNA-miRNA-mRNA regulatory networks using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed the regulatory relationships among these three lncRNAs and AD. Results: The results showed that there were 120 significantly different ac4C peaks located on 102 lncRNAs in AD, of which 55 were hyperacetylated and 47 were hypoacetylated. Simultaneously, 231 differentially expressed lncRNAs were identified, including 138 upregulated lncRNAs and 93 downregulated lncRNAs. Moreover, 3 lncRNAs, lncRNA Gm26508, lncRNA A430046D13Rik, and lncRNA 9530059O14Rik, showed significant changes in both the ac4C and RNA levels using conjoint analysis. Conclusion: The abundance of lncRNA ac4C modification is significantly different in AD and indicates that lncRNA ac4C is associated with the occurrence and development of AD, which could provide a basis for further exploration of the related regulatory mechanisms. Show more

Keywords: ac4C acetylation, Alzheimer’s disease, high-throughput sequencing, lncRNAs

DOI: 10.3233/JAD-220564

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1659-1675, 2022

Authors: Ng, Ted Kheng Siang | Tan, Xiang Ren | Todd, Michael | Chen, Angela Chia-Chen | Feng, Lei | Lu, Yanxia | Yu, Fang | Kua, Ee Heok | Mahendran, Rathi

Article Type: Research Article

Abstract: Background: Few randomized controlled trials (RCTs) investigated the effects of mindfulness intervention on affective and cognitive symptoms in older adults with mild cognitive impairment (MCI). Furthermore, no RCTs on mindfulness followed participants beyond two years. Objective: To examine the longitudinal effects of a mindful awareness practice (MAP) intervention on depressive, anxiety, and cognitive symptoms in MCI. Methods: In this parallel-arm and assessor-blinded RCT, 55 community-dwelling older adults with MCI were randomized into the MAP or active control, i.e., health education program (HEP). Intervention sessions were conducted weekly for three months and monthly for the subsequent six …months. Assessments and follow-up were conducted at baseline, 3-month, 9-month, and 5-year time points. Depressive, anxiety, and cognitive symptoms were measured using the Geriatric Depression Scale-15 (GDS-15), Geriatric Anxiety Inventory-20 (GAI-20), and Mini-Mental State Examination (MMSE), respectively. Linear-mixed models, following the intention-to-treat principle, were used for data analyses. Results: A total of 55 participants aged 60 to 86 (Mean age: 71.3±6 years old) was recruited, with n  = 28 allocated to the MAP arm and n  = 27 allocated to the HEP arm. Compared to HEP, GDS-15, GAI-20, and MMSE scores did not differ significantly in MAP during follow-ups. Conclusion: Compared to HEP, MAP did not improve affective symptoms nor delay deteriorations in general cognition in community-dwelling older adults with MCI. Compared to our previous findings showing domain-specific improvements in MAP over HEP in attention and memory up to 9 months, this study highlights the importance of examining domain-specificity using detailed cognitive measures in non-pharmacological intervention with MCI. Show more

Keywords: Geriatric anxiety inventory, health education, mild cognitive impairment, mindfulness, mini-mental state examination, geriatric depression scale, non-pharmacological intervention, preclinical dementia

DOI: 10.3233/JAD-220641

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1677-1688, 2022

Authors: Ayton, Darshini | Pirotta, Stephanie | Morello, Renata | Rosenich, Emily | Barton, Chris | Lavale, Alexandra | Pase, Matthew P. | Maruff, Paul | Yassi, Nawaf | Brodtmann, Amy | Lim, Yen Ying | Barker, Anna

Article Type: Research Article

Abstract: Background: The BetterBrains Randomized Controlled Trial (RCT) will evaluate the effectiveness of an online, person-centered, risk factor management, coaching intervention in community-dwelling, healthy adults at risk of cognitive decline. Multi-component interventions are challenging to evaluate due to program complexity and personalization to individual needs and contexts. This paper describes a multi-level process evaluation conducted alongside the BetterBrains RCT. Objective: To understand how and why the BetterBrains intervention was effective or ineffective at reducing cognitive decline in healthy adults whilst considering the context in which it was implemented. Methods: 1,510 non cognitively-deteriorated community-dwelling adults aged 40–70 years …old at risk of cognitive decline will be recruited and randomly assigned to the intervention or control group. All BetterBrains intervention participants, coaches, and the research team will be included in the evaluation. A mixed-methods design will be used, guided by The Framework for Implementation Fidelity and the program logic model. Data will be sourced from interviews, focus groups, surveys, BetterBrains coach notes, participant weekly check-in surveys, and audio recordings of intervention coaching sessions. Quantitative data will be analyzed via descriptive and inferential statistics and qualitative data will be analyzed using content and thematic analysis. Results: The process evaluation will provide information about contextual and influencing factors related to the implementation of BetterBrains and the RCT outcomes. Conclusion: Understanding how BetterBrains was implemented and its associated impacts will inform the translation of the program into community and clinical settings, providing easy access to online, personalized dementia prevention services. Show more

Keywords: Chronic disease prevention, cognitive decline, implementation, process evaluation

DOI: 10.3233/JAD-220341

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1689-1703, 2022

Authors: Restifo, Daniel | Zhao, Chen | Kamel, Hooman | Iadecola, Costantino | Parikh, Neal S.

Article Type: Research Article

Abstract: Background: The detrimental impact of tobacco smoking on brain health is well recognized. Objective: To evaluate whether smoking acts synergistically with hypertension and diabetes to influence cognitive performance. Methods: We performed a cross-sectional analysis using the US National Health and Nutrition Examination Survey. Participants were tested for serum cotinine, a validated cigarette smoking/exposure biomarker, and had standardized blood pressure and hemoglobin A1c measurements. Participants were administered four cognitive tests: Digit Symbol Substitution (DSST), Animal Fluency, Immediate Recall, and Delayed Recall. Multivariable linear regression models adjusted for demographics and confounders evaluated the association of cotinine with cognition. …Interaction testing evaluated effect modification by hypertension, diabetes, and their continuous measures (systolic blood pressure and hemoglobin A1c). Results: For 3,007 participants, mean age was 69.4 years; 54% were women. Using cotinine levels, 14.9% of participants were categorized as active smokers. Higher cotinine levels were associated with worse DSST performance when modeling cotinine as a continuous variable (β, -0.70; 95% CI, -1.11, -0.29; p  < 0.01) and when categorizing participants as active smokers (β, -5.63; 95% CI, -9.70, -1.56; p  < 0.01). Cotinine was not associated with fluency or memory. Effect modification by hypertension and diabetes were absent, except that cotinine was associated with worse Immediate Recall at lower blood pressures. Conclusion: Higher levels of a smoking and secondhand exposure biomarker were associated with worse cognitive performance on a multidomain test. Overall, the relationship of cotinine with cognition was not contingent on or amplified by hypertension or diabetes; smoking is detrimental for brain health irrespective of these comorbidities. Show more

Keywords: Cigarette smoking, cognition, cotinine, diabetes, hypertension

DOI: 10.3233/JAD-220647

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1705-1712, 2022

Authors: Musaeus, Christian Sandøe | Waldemar, Gunhild | Andersen, Birgitte Bo | Høgh, Peter | Kidmose, Preben | Hemmsen, Martin Christian | Rank, Mike Lind | Kjær, Troels Wesenberg | Frederiksen, Kristian Steen

Article Type: Research Article

Abstract: Background: Previous studies have reported that epileptiform activity may be detectible in nearly half of patients with Alzheimer’s disease (AD) on long-term electroencephalographic (EEG) recordings. However, such recordings can be uncomfortable, expensive, and difficult. Ear-EEG has shown promising results for long-term EEG monitoring, but it has not been used in patients with AD. Objective: To investigate if ear-EEG is a feasible method for long-term EEG monitoring in patients with AD. Methods: In this longitudinal, single-group feasibility study, ten patients with mild to moderate AD were recruited. A total of three ear-EEG recordings of up to 48 …hours three months apart for six months were planned. Results: All patients managed to wear the ear-EEG for at least 24 hours and at least one full night. A total of 19 ear-EEG recordings were performed (self-reported recording, mean: 37.15 hours (SD: 8.96 hours)). After automatic pre-processing, a mean of 27.37 hours (SD: 7.19 hours) of data with acceptable quality in at least one electrode in each ear was found. Seven out of ten participants experienced mild adverse events. Six of the patients did not complete the study with three patients not wanting to wear the ear-EEG anymore due to adverse events. Conclusion: It is feasible and safe to use ear-EEG for long-term EEG monitoring in patients with AD. Minor adjustments to the equipment may improve the comfort for the participants. Show more

Keywords: Alzheimer’s disease, ear-EEG, electroencephalography, long-term EEG, wearable

DOI: 10.3233/JAD-220491

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1713-1723, 2022

Authors: Bartels, Claudia | Abdel-Hamid, Mona | Wiltfang, Jens | Schneider, Anja | Belz, Michael

Article Type: Research Article

Abstract: Background: The multimodal CORDIAL treatment concept for mild dementia, combining cognitive rehabilitation, cognitive behavioral and humanistic psychology interventions, has proven its feasibility and demonstrated a reduction of depressive symptoms in individual dyadic/triadic settings. Objective: We investigate antidepressant effects of an adapted group-based CORDIAL program in clinical routine care. Methods: During 2013 and 2017, 51 outpatients with mild dementia (45% female, mean age 72.4 years, 67% Alzheimer’s dementia, mean MMST 24.8) periodically received a modified CORDIAL group treatment as part of our regular outpatient care. Treatment comprised 10 bi-weekly sessions, partly involving caregivers. Systematic pre- and post-treatment …assessments of clinical routine data were evaluated retrospectively (median time-interval of 6.6 months). Results: Depressive symptoms as measured by the Geriatric Depression Scale significantly decreased over time (p  = 0.007, Cohen’s d  = 0.39), and irrespective of gender. Patients with longer disease duration before treatment start showed significantly higher initial levels of depressive symptoms (p  = 0.044), followed by a reduction to a level of those with shorter disease duration (ns ). Most secondary outcomes (cognitive symptoms, disease severity, quality of life, caregiver burden) remained unchanged (ns ), while competence in activities of daily living declined from pre- to post-measurement (p  = 0.033). Conclusion: A group-based CORDIAL treatment is feasible in a clinical routine setting and demonstrated antidepressant effects comparable to those of the individual treatment design, further suggesting its implementation in regular care. Future trials might also investigate its potentially preventive effects by reducing depressive symptoms in pre-dementia stages, even at a subsyndromal level. Show more

Keywords: Dementia, depression, cognitive rehabilitation, cognitive behavioral therapy, reminiscence, group therapy, activities of daily living, caregiver burden

DOI: 10.3233/JAD-220578

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1725-1737, 2022