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

Authors: Laton, Jorne | Van Schependom, Jeroen | Goossens, Joery | Wiels, Wietse | Sieben, Anne | De Deyn, Peter Paul | Goeman, Johan | Streffer, Johannes | van der Zee, Julie | Martin, Jean-Jacques | Van Broeckhoven, Christine | De Vos, Maarten | Bjerke, Maria | Nagels, Guy | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Distinguishing between Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy. Objective: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis. Methods: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42 , T-tau, P-tau181 , and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four …regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG). Results: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95%. Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD. Conclusion: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebrospinal fluid, dementia, EEG, frontotemporal dementia, neurofilament light, random forest, tau protein

DOI: 10.3233/JAD-220693

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1739-1747, 2022

Authors: Ren, Shuhua | Hu, Jingchao | Huang, Lin | Li, Junpeng | Jiang, Donglang | Hua, Fengchun | Guan, Yihui | Guo, Qihao | Xie, Fang | Huang, Qi

Article Type: Research Article

Abstract: Background: Subjects with subjective cognitive decline (SCD) are proposed as a potential population to screen for Alzheimer’s disease (AD). Objective: Investigating brain topologies would help to mine the neuromechanisms of SCD and provide new insights into the pathogenesis of AD. Methods: Objectively cognitively unimpaired subjects from communities who underwent resting-state BOLD-fMRI and clinical assessments were included. The subjects were categorized into SCD and normal control (NC) groups according to whether they exhibited self-perceived cognitive decline and were worried about it. The minimum spanning tree (MST) of the functional brain network was calculated for each subject, based …on which the efficiency and centrality of the brain network organization were explored. Hippocampal/parahippocampal volumes were also detected to reveal whether the early neurodegeneration of AD could be seen in SCD. Results: A total of 49 subjects in NC and 95 subjects in SCD group were included in this study. We found the efficiency and centrality of brain network organization, as well as the hippocampal/parahippocampal volume were preserved in SCD. Besides, SCD exhibited normal cognitions, including memory, language, and execution, but increased depressive and anxious levels. Interestingly, language and execution, instead of memory, showed a significant positive correlation with the maximum betweenness centrality of the functional brain organization and hippocampal/parahippocampal volume. Neither depressive nor anxious scales exhibited correlations with the brain functional topologies or hippocampal/parahippocampal volume. Conclusion: SCD exhibited preserved efficiency and centrality of brain organization. In clinical practice, language and execution as well as depression and anxiety should be paid attention in SCD. Show more

Keywords: Alzheimer’s disease, functional brain topologies, hippocampal volume, minimum spanning tree, subjective cognitive decline

DOI: 10.3233/JAD-220527

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1749-1759, 2022

Authors: Ganapathi, Aarthi S. | Glatt, Ryan M. | Bookheimer, Tess H. | Popa, Emily S. | Ingemanson, Morgan L. | Richards, Casey J. | Hodes, John F. | Pierce, Kyron P. | Slyapich, Colby B. | Iqbal, Fatima | Mattinson, Jenna | Lampa, Melanie G. | Gill, Jaya M. | Tongson, Ynez M. | Wong, Claudia L. | Kim, Mihae | Porter, Verna R. | Kesari, Santosh | Meysami, Somayeh | Miller, Karen J. | Bramen, Jennifer E. | Merrill, David A. | Siddarth, Prabha

Article Type: Research Article

Abstract: Background: Distinguishing between subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia in a scalable, accessible way is important to promote earlier detection and intervention. Objective: We investigated diagnostic categorization using an FDA-cleared quantitative electroencephalographic/event-related potential (qEEG/ERP)-based cognitive testing system (eVox® by Evoke Neuroscience) combined with an automated volumetric magnetic resonance imaging (vMRI) tool (Neuroreader® by Brainreader). Methods: Patients who self-presented with memory complaints were assigned to a diagnostic category by dementia specialists based on clinical history, neurologic exam, neuropsychological testing, and laboratory results. In addition, qEEG/ERP (n  = 161) and quantitative vMRI (n … = 111) data were obtained. A multinomial logistic regression model was used to determine significant predictors of cognitive diagnostic category (SCD, MCI, or dementia) using all available qEEG/ERP features and MRI volumes as the independent variables and controlling for demographic variables. Area under the Receiver Operating Characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the prediction models. Results: The qEEG/ERP measures of Reaction Time, Commission Errors, and P300b Amplitude were significant predictors (AUC = 0.79) of cognitive category. Diagnostic accuracy increased when volumetric MRI measures, specifically left temporal lobe volume, were added to the model (AUC = 0.87). Conclusion: This study demonstrates the potential of a primarily physiological diagnostic model for differentiating SCD, MCI, and dementia using qEEG/ERP-based cognitive testing, especially when combined with volumetric brain MRI. The accessibility of qEEG/ERP and vMRI means that these tools can be used as adjuncts to clinical assessments to help increase the diagnostic certainty of SCD, MCI, and dementia. Show more

Keywords: Dementia, electroencephalography, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-220616

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1761-1769, 2022

Authors: Giraldo, Diana L. | Smith, Robert E. | Struyfs, Hanne | Niemantsverdriet, Ellis | De Roeck, Ellen | Bjerke, Maria | Engelborghs, Sebastiaan | Romero, Eduardo | Sijbers, Jan | Jeurissen, Ben

Article Type: Research Article

Abstract: Background: Most studies using diffusion-weighted MRI (DW-MRI) in Alzheimer’s disease (AD) have focused their analyses on white matter (WM) microstructural changes using the diffusion (kurtosis) tensor model. Although recent works have addressed some limitations of the tensor model, such as the representation of crossing fibers and partial volume effects with cerebrospinal fluid (CSF), the focus remains in modeling and analyzing the WM. Objective: In this work, we present a brain analysis approach for DW-MRI that disentangles multiple tissue compartments as well as micro- and macroscopic effects to investigate differences between groups of subjects in the AD continuum and …controls. Methods: By means of the multi-tissue constrained spherical deconvolution of multi-shell DW-MRI, underlying brain tissue is modeled with a WM fiber orientation distribution function along with the contributions of gray matter (GM) and CSF to the diffusion signal. From this multi-tissue model, a set of measures capturing tissue diffusivity properties and morphology are extracted. Group differences were interrogated following fixel-, voxel-, and tensor-based morphometry approaches while including strong FWE control across multiple comparisons. Results: Abnormalities related to AD stages were detected in WM tracts including the splenium, cingulum, longitudinal fasciculi, and corticospinal tract. Changes in tissue composition were identified, particularly in the medial temporal lobe and superior longitudinal fasciculus. Conclusion: This analysis framework constitutes a comprehensive approach allowing simultaneous macro and microscopic assessment of WM, GM, and CSF, from a single DW-MRI dataset. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cognitive dysfunction, dementia, diffusion MRI, gray matter, white matter

DOI: 10.3233/JAD-220551

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1771-1791, 2022

Authors: Gaubert, Fanny | Borg, Céline | Chainay, Hanna

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) negatively impacts patients’ ability to make advantageous decisions, i.e., a core ability contributing to the preservation of autonomy. Objective: The present study aims to analyze the changes that occur in the decision-making competence (DMC) in AD patients and to determine if these changes are related to the deterioration of executive functions and working memory. Method: To this end, 20 patients with AD and 20 elderly control adults were assessed using executive, working memory, and DMC tasks. The latter comprised the Iowa Gambling Task (IGT) and a scenarios task based on situations inspired …by everyday life and performed under conditions of risk and ambiguity. Results: Results revealed lower performances in AD patients than in elderly control adults for all the tasks assessing cognitive functions. The AD patients also made more strategy changes during the IGT. In the scenarios tasks, the two groups took as many ambiguous or risky decisions, but AD patients tended to take more risks in the context of gain than elderly control adults did. Switching and updating ability, as well as working memory, appeared to be involved in decisions in tasks inspired by everyday life, while inhibition was more related to the IGT performances. Conclusion: Working memory and executive functions seem to be involved in decision-making, but in different ways in gambling and daily-life situations. Show more

Keywords: Alzheimer’s disease, decision making, executive function, working memory

DOI: 10.3233/JAD-220581

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1793-1815, 2022

Authors: Kleiman, Michael J. | Chang, Lun-Ching | Galvin, James E.

Article Type: Research Article

Abstract: Background: It is difficult to assess brain health status and risk of cognitive impairment, particularly at the initial evaluation. To address this, we developed the Brain Health Platform to quantify brain health and identify Alzheimer’s disease and related disorders (ADRD) risk factors by combining a measure of brain health: the Resilience Index (RI), a measure of risk of ADRD; the Vulnerability Index (VI); and the Number-Symbol Coding Task (NSCT), a measure of brain performance. Objective: The Brain Health Platform is intended to be easily and quickly administered, providing an overview of a patient’s risk of developing future impairment …based on modifiable and non-modifiable factors as well as current cognitive performance. Methods: This cross-sectional study comprehensively evaluated 230 participants (71 controls, 71 mild cognitive impairment, 88 ADRD). VI and RI scores were derived from physical assessments, lifestyle questionnaires, demographics, medical history, and neuropsychological examination including the NSCT. Results: Individuals with abnormal scores were 95.7% likely to be impaired, with a misclassification rate of 9.7%. The combined model had excellent discrimination (AUC:0.923±0.053; p  < 0.001), performing better than the Montreal Cognitive Assessment. Conclusion: The Brain Health Platform combines measures of resilience, vulnerability, and performance to provide a cross-sectional snapshot of overall brain health. The Brain Health Platform can effectively and accurately identify even the very mildest impairments due to ADRD, leveraging brief yet powerful and actionable indices of brain health and risk that could be used to develop personalized, precision medicine-like interventions. Show more

Keywords: Alzheimer’s disease, brain health, cognitive assessment, dementia, dementia with Lewy bodies, mild cognitive impairment, resilience, screening, vascular cognitive impairment, vulnerability

DOI: 10.3233/JAD-220927

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1817-1830, 2022

Authors: Whitehouse, Peter J. | George, Daniel R.

Article Type: Book Review

DOI: 10.3233/JAD-221066

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1831-1833, 2022

Article Type: Other

DOI: 10.3233/JAD-229012

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1835-1849, 2022

Authors: Prema, Asokan | Justin Thenmozhi, Arokiasamy | Manivasagam, Thamilarasan | Mohamed Essa, Musthafa | Guillemin, Gilles J.

Article Type: Correction

DOI: 10.3233/JAD-229017

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1851-1852, 2022