Journal of Alzheimer's Disease - Volume 99, issue 1

Authors: Yoo, Han Soo | Kim, Han-Kyeol | Lee, Jae-Hoon | Chun, Joong-Hyun | Lee, Hye Sun | Grothe, Michel J. | Teipel, Stefan | Cavedo, Enrica | Vergallo, Andrea | Hampel, Harald | Ryu, Young Hoon | Cho, Hanna | Lyoo, Chul Hyoung

Article Type: Research Article

Abstract: Background: Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer’s disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. Objective: To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. Methods: In this retrospective cohort study, we enrolled 113 subjects (38 amyloid [Aβ]-negative cognitively unimpaired, 6 Aβ-positive cognitively unimpaired, 39 with prodromal AD, and 30 with AD dementia) who performed brain MRI for BF volume and cortical thickness, 18 F-florbetaben PET for Aβ, 18 F-flortaucipir PET for tau, and detailed cognitive …testing longitudinally. We investigated the baseline and longitudinal association of BF volume with Aβ and tau standardized uptake value ratio and cognition. Results: Cross-sectionally, lower BF volume was not independently associated with higher cortical Aβ, but it was associated with tau burden. Tau burden in the orbitofrontal, insular, lateral temporal, inferior temporo-occipital, and anterior cingulate cortices were associated with progressive BF atrophy. Lower BF volume was associated with faster Aβ accumulation, mainly in the prefrontal, anterior temporal, cingulate, and medial occipital cortices. BF volume was associated with progressive decline in language and memory functions regardless of baseline Aβ and tau burden. Conclusions: Tau deposition affected progressive BF atrophy, which in turn accelerated amyloid deposition, leading to a vicious cycle. Also, lower baseline BF volume independently predicted deterioration in cognitive function. Show more

Keywords: Alzheimer’s disease, amyloid-beta, basal forebrain, cognition, tau

DOI: 10.3233/JAD-230975

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 145-159, 2024

Authors: Marr, Calum | McDowell, Bethany | Holmes, Clive | Edwards, Christopher J. | Cardwell, Christopher | McHenry, Michelle | Meenagh, Gary | Teeling, Jessica L. | McGuinness, Bernadette

Article Type: Research Article

Abstract: Background: Evidence suggests that TNF inhibitors (TNFi) used to treat rheumatoid arthritis (RA) may protect against Alzheimer’s disease progression by reducing inflammation. Objective: To investigate whether RA patients with mild cognitive impairment (MCI) being treated with a TNFi show slower cognitive decline than those being treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Methods: 251 participants with RA and MCI taking either a csDMARD (N  = 157) or a TNFi (N  = 94) completed cognitive assessments at baseline and 6-month intervals for 18 months. It was hypothesized that those taking TNFis would show less decline on the …primary outcome of Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) and the secondary outcome of Montreal Cognitive Assessment (MoCA). Results: No significant changes in FCSRT-IR scores were observed in either treatment group. There was no significant difference in FCSRT-IR between treatment groups at 18 months after adjusting for baseline (mean difference = 0.5, 95% CI = –1.3, 2.3). There was also no difference in MoCA score (mean difference = 0.4, 95% CI = –0.4, 1.3). Conclusions: There was no cognitive decline in participants with MCI being treated with TNFis and csDMARDs, raising the possibility both classes of drug may be protective. Future studies should consider whether controlling inflammatory diseases using any approach is more important than a specific therapeutic intervention. Show more

Keywords: Alzheimer’s disease, inflammation, mild cognitive impairment, rheumatoid arthritis, tumor necrosis factor-alpha

DOI: 10.3233/JAD-231329

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 161-175, 2024

Authors: Sighinolfi, Giovanni | Mitolo, Micaela | Pizzagalli, Fabrizio | Stanzani-Maserati, Michelangelo | Remondini, Daniel | Rochat, Magali Jane | Cantoni, Elena | Venturi, Greta | Vornetti, Gianfranco | Bartiromo, Fiorina | Capellari, Sabina | Liguori, Rocco | Tonon, Caterina | Testa, Claudia | Lodi, Raffaele

Article Type: Research Article

Abstract: Background: Being able to differentiate mild cognitive impairment (MCI) patients who would eventually convert (MCIc) to Alzheimer’s disease (AD) from those who would not (MCInc) is a key challenge for prognosis. Objective: This study aimed to investigate the ability of sulcal morphometry to predict MCI progression to AD, dedicating special attention to an accurate identification of sulci. Methods: Twenty-five AD patients, thirty-seven MCI and twenty-five healthy controls (HC) underwent a brain-MR protocol (1.5T scanner) including a high-resolution T1-weighted sequence. MCI patients underwent a neuropsychological assessment at baseline and were clinically re-evaluated after a mean of 2.3 …years. At follow-up, 12 MCI were classified as MCInc and 25 as MCIc. Sulcal morphometry was investigated using the BrainVISA framework. Consistency of sulci across subjects was ensured by visual inspection and manual correction of the automatic labelling in each subject. Sulcal surface, depth, length, and width were retrieved from 106 sulci. Features were compared across groups and their classification accuracy in predicting MCI conversion was tested. Potential relationships between sulcal features and cognitive scores were explored using Spearman’s correlation. Results: The width of sulci in the temporo-occipital region strongly differentiated between each pair of groups. Comparing MCIc and MCInc, the width of several sulci in the bilateral temporo-occipital and left frontal areas was significantly altered. Higher width of frontal sulci was associated with worse performances in short-term verbal memory and phonemic fluency. Conclusions: Sulcal morphometry emerged as a strong tool for differentiating HC, MCI, and AD, demonstrating its potential prognostic value for the MCI population. Show more

Keywords: Alzheimer’s disease, brain sulci, cortical thickness, MCI conversion, mild cognitive impairment, sulcalmorphometry

DOI: 10.3233/JAD-231192

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 177-190, 2024

Authors: Tahami Monfared, Amir Abbas | Khachatryan, Artak | Hummel, Noemi | Kopiec, Agnieszka | Martinez, Marta | Zhang, Raymond | Zhang, Quanwu

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and mild cognitive impairment (MCI) have negative quality of life (QoL) and economic impacts on patients and their caregivers and may increase along the disease continuum from MCI to mild, moderate, and severe AD. Objective: To assess how patient and caregiver QoL, indirect and intangible costs are associated with MCI and AD severity. Methods: An on-line survey of physician-identified patient-caregiver dyads living in the United States was conducted from June–October 2022 and included questions to both patients and their caregivers. Dementia Quality of Life Proxy, the Care-related Quality of Life, Work Productivity …and Activity Impairment, and Dependence scale were incorporated into the survey. Regression analyses investigated the association between disease severity and QoL and cost outcomes with adjustment for baseline characteristics. Results: One-hundred patient-caregiver dyads were assessed with the survey (MCI, n  = 27; mild AD, n  = 27; moderate AD, n  = 25; severe AD, n  = 21). Decreased QoL was found with worsening severity in patients (p  < 0.01) and in unpaid (informal) caregivers (n  = 79; p  = 0.02). Dependence increased with disease severity (p  < 0.01). Advanced disease severity was associated with higher costs to employers (p  = 0.04), but not with indirect costs to caregivers. Patient and unpaid caregiver intangible costs increased with disease severity (p  < 0.01). A significant trend of higher summed costs (indirect costs to caregivers, costs to employers, intangible costs to patients and caregivers) in more severe AD was observed (p  < 0.01). Conclusions: Patient QoL and functional independence and unpaid caregiver QoL decrease as AD severity increases. Intangible costs to patients and summed costs increase with disease severity and are highest in severe AD. Show more

Keywords: Alzheimer’s disease, cost of illness, employer health costs, global burden of disease, health expenditure, indirect expenditure, intangible cost, mild cognitive impairment, quality of life

DOI: 10.3233/JAD-231259

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 191-206, 2024

Authors: Boujelbane, Mohamed Ali | Trabelsi, Khaled | Salem, Atef | Ammar, Achraf | Glenn, Jordan M. | Boukhris, Omar | AlRashid, Maha M. | Jahrami, Haitham | Chtourou, Hamdi

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and mild cognitive impairment (MCI) progress silently, making early diagnosis challenging, especially in less educated populations. The visual paired comparison (VPC) task, utilizing eye-tracking movement (ETM) technology, offers a promising alternative for early detection of memory decline. Objective: This systematic review and meta-analysis evaluated the efficacy of the VPC task, utilizing ETM as a tool for assessing age-related cognitive changes. Methods: A comprehensive search across five databases and grey literature focused on healthy and impaired memory participants assessed through the ETM-based VPC task. The primary outcomes were novelty preference scores and eye movement …metrics. The risk of bias of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Random-effects meta-analyses calculated Hedges’ g effect size. Sensitivity and specificity of the VPC were meta-analytically pooled. Results: The systematic review included 12 articles, involving 1,022 participants (aged 18 to 90 years, with education ranging from 6.5 to 20.0 years), with a low risk of bias and minimal applicability concerns across all items. Five studies contributed to the meta-analysis, revealing a significant effect favoring the VPC task for recognition memory detection (k  = 9, g  = –1.03). Pooled sensitivity and specificity analyses demonstrated VPC effectiveness as a recognition memory assessment tool (0.84 and 0.75, respectively). Conclusions: The VPC task, utilizing ETM, may serve as a biomarker for early memory decline detection. Its use as a digital eye-tracking tool presents a possible alternative to traditional tests, warranting further research for application in neurodegenerative disease diagnosis. Show more

Keywords: Alzheimer’s disease, cognition, dementia, eye movements, novelty preference score, sensitivity, specificity

DOI: 10.3233/JAD-240028

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 207-221, 2024

Authors: Choi, Yu Yong | Lee, Jang Jae | te Nijenhuis, Jan | Choi, Kyu Yeong | Park, Jongseong | Ok, Jongmyoung | Choo, IL Han | Kim, Hoowon | Song, Min-Kyung | Choi, Seong-Min | Cho, Soo Hyun | Choe, Youngshik | Kim, Byeong C. | Lee, Kun Ho

Article Type: Research Article

Abstract: Background: We previously demonstrated the validity of a regression model that included ethnicity as a novel predictor for predicting normative brain volumes in old age. The model was optimized using brain volumes measured with a standard tool FreeSurfer. Objective: Here we further verified the prediction model using newly estimated brain volumes from Neuro I, a quantitative brain analysis system developed for Korean populations. Methods: Lobar and subcortical volumes were estimated from MRI images of 1,629 normal Korean and 786 Caucasian subjects (age range 59–89) and were predicted in linear regression from ethnicity, age, sex, intracranial volume, …magnetic field strength, and scanner manufacturers. Results: In the regression model predicting the new volumes, ethnicity was again a substantial predictor in most regions. Additionally, the model-based z-scores of regions were calculated for 428 AD patients and the matched controls, and then employed for diagnostic classification. When the AD classifier adopted the z-scores adjusted for ethnicity, the diagnostic accuracy has noticeably improved (AUC = 0.85, Δ AUC = + 0.04, D  = 4.10, p  < 0.001). Conclusions: Our results suggest that the prediction model remains robust across different measurement tool, and ethnicity significantly contributes to the establishment of norms for brain volumes and the development of a diagnostic system for neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, brain aging, ethnic difference, magnetic resonance imaging, norm

DOI: 10.3233/JAD-231182

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 223-240, 2024

Authors: Ngo, Sang | Jackson, Ashley J. | Manivannan, Madhumitha | Young, J. Clayton | Leggins, Brandon | Cryns, Noah G. | Tran, Sheila T. | Grant, Harli E. | Knudtson, Marguerite V. | Chiong, Winston

Article Type: Research Article

Abstract: Background: Whereas clinical experience in dementia indicates high risk for financial mismanagement, there has been little formal study of real world financial errors in dementia. Objective: We aimed to compare caregiver-reported financial mistakes among people with Alzheimer’s disease, behavioral variant frontotemporal dementia (bvFTD), and primary progressive aphasia (PPA). Methods: Caregivers reported whether participants with dementia had made financial mistakes within the last year; and if so, categorized these as resulting from: (a) being too trusting or gullible, (b) being wasteful or careless with money, or (c) trouble with memory. In a pre-registered analysis https://archive.org/details/osf-registrations-vupj7-v1 ), we …examined the hypotheses that (1) financial mistakes due to impaired socioemotional function and diminished sensitivity to negative outcomes are more prevalent in bvFTD than in Alzheimer’s disease, and (2) financial mistakes due to memory are more prevalent in Alzheimer’s disease than in bvFTD. Exploratory analyses addressed vulnerability in PPA and brain-behavior relationships using voxel-based morphometry. Results: Concordant with our first hypothesis, bvFTD was more strongly associated than Alzheimer’s disease with mistakes due to being too trusting/gullible or wasteful/careless; contrary to our second hypothesis, both groups were similarly likely to make mistakes due to memory. No differences were found between Alzheimer’s disease and PPA. Exploratory analyses indicated associations between financial errors and atrophy in right prefrontal and insular cortex. Conclusions: Our findings cohere with documented socioemotional and valuation impairments in bvFTD, and with research indicating comparable memory impairment between bvFTD and Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, decision making, financial activities, financial management, frontotemporal dementia, primary progressive aphasia

DOI: 10.3233/JAD-231021

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 251-262, 2024

Authors: Chandrasekaran, Ganesh | Xie, Sharon X.

Article Type: Research Article

Abstract: Background: Missing data is prevalent in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). It is common to deal with missingness by removing subjects with missing entries prior to statistical analysis; however, this can lead to significant efficiency loss and sometimes bias. It has yet to be demonstrated that the imputation approach to handling this issue can be valuable in some longitudinal regression settings. Objective: The purpose of this study is to demonstrate the importance of imputation and how imputation is correctly done in ADNI by analyzing longitudinal Alzheimer’s Disease Assessment Scale –Cognitive Subscale 13 (ADAS-Cog 13) scores and their …association with baseline patient characteristics. Methods: We studied 1,063 subjects in ADNI with mild cognitive impairment. Longitudinal ADAS-Cog 13 scores were modeled with a linear mixed-effects model with baseline clinical and demographic characteristics as predictors. The model estimates obtained without imputation were compared with those obtained after imputation with Multiple Imputation by Chained Equations (MICE). We justify application of MICE by investigating the missing data mechanism and model assumptions. We also assess robustness of the results to the choice of imputation method. Results: The fixed-effects estimates of the linear mixed-effects model after imputation with MICE yield valid, tighter confidence intervals, thus improving the efficiency of the analysis when compared to the analysis done without imputation. Conclusions: Our study demonstrates the importance of accounting for missing data in ADNI. When deciding to perform imputation, care should be taken in choosing the approach, as an invalid one can compromise the statistical analyses. Show more

Keywords: Alzheimer’s disease, biomarkers, imputation, longitudinal study, missing data

DOI: 10.3233/JAD-231047

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 263-277, 2024

Authors: Kim, Minjae | Song, Yoo Sung | Han, Kyunghwa | Bae, Yun Jung | Han, Ji Won | Kim, Ki Woong

Article Type: Research Article

Abstract: Background: Impaired glymphatic flow on the Alzheimer’s disease (AD) spectrum may be evaluated using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Objective: We aimed to validate impaired glymphatic flow and explore its association with gray matter volume, cognitive status, and cerebral amyloid deposition on the AD spectrum. Methods: 80 participants (mean age, 76.9±8.5 years; 57 women) with AD (n  = 65) and cognitively normal (CN) (n  = 15) who underwent 3T brain MRI including DTI and/or amyloid PET were included. After adjusting for age, sex, apolipoprotein E status, and burden of white matter hyperintensities, the ALPS-index …was compared according to the AD spectrum. The association between the ALPS-index and gray matter volume, cognitive status, and quantitative amyloid from PET was assessed. Results: The ALPS-index in the AD was significantly lower (mean, 1.476; 95% CI, 1.395–1.556) than in the CN (1.784;1.615–1.952; p  = 0.026). Volumes of the entorhinal cortex, hippocampus, temporal pole, and primary motor cortex showed significant associations with the ALPS-index (all, p  < 0.05). There was a positive correlation between the ALPS-index and MMSE score (partial r  = 0.435; p  < 0.001), but there was no significant correlation between the ALPS-index and amyloid SUVRs (all, p  > 0.05). Conclusions: Decreased glymphatic flow measured by DTI-ALPS in AD may serve as a marker of neurodegeneration correlating with structural atrophy and cognitive decline. Show more

Keywords: Alzheimer’s disease, amyloid PET, diffusion tensor, glymphatic function, volumetry

DOI: 10.3233/JAD-231131

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 279-290, 2024

Authors: Butler, Tracy | Wang, Xiuyuan | Chiang, Gloria | Xi, Ke | Niogi, Sumit | Glodzik, Lidia | Li, Yi | Razlighi, Qolamreza Ray | Zhou, Liangdong | Hojjati, Seyed Hani | Ozsahin, Ilker | Mao, Xiangling | Maloney, Thomas | Tanzi, Emily | Rahmouni, Nesrine | Tissot, Cécile | Lussier, Firoza | Shah, Sudhin | Shungu, Dikoma | Gupta, Ajay | De Leon, Mony | Mozley, P. David | Pascoal, Tharick A. | Rosa-Neto, Pedro

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. Objective: To define age and AD associations of brainstem TSPO PET signal in humans. Methods: We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem …in 71 subjects (43 controls scanned using 11 C-PK11195; 20 controls and 8 AD subjects scanned using 11 C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. Results: TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p  = 0.001) and in AD subjects versus controls (p  = 0.004). In cortex, TSPO expression was increased with aging (p  = 0.030) and AD (p  = 0.033). Conclusions: Decreased IC TSPO expression with aging and AD—an opposite pattern than in cortex—highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed. Show more

Keywords: Alzheimer’s disease, inferior colliculus, inflammation, neuroinflammation, reticular formation, TSPO PET

DOI: 10.3233/JAD-231312

Citation: Journal of Alzheimer's Disease, vol. 99, no. 1, pp. 307-319, 2024