Journal of Alzheimer's Disease - Volume 101, issue 1

Authors: Zhang, Yahui | Li, Yulin | Song, Shangchen | Li, Zhigang | Lu, Minggen | Shan, Guogen

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) patients are at a high risk of developing Alzheimer’s disease and related dementias (ADRD) at an estimated annual rate above 10%. It is clinically and practically important to accurately predict MCI-to-dementia conversion time. Objective: It is clinically and practically important to accurately predict MCI-to-dementia conversion time by using easily available clinical data. Methods: The dementia diagnosis often falls between two clinical visits, and such survival outcome is known as interval-censored data. We utilized the semi-parametric model and the random forest model for interval-censored data in conjunction with a variable selection approach …to select important measures for predicting the conversion time from MCI to dementia. Two large AD cohort data sets were used to build, validate, and test the predictive model. Results: We found that the semi-parametric model can improve the prediction of the conversion time for patients with MCI-to-dementia conversion, and it also has good predictive performance for all patients. Conclusions: Interval-censored data should be analyzed by using the models that were developed for interval- censored data to improve the model performance. Show more

Keywords: Alzheimer’s disease, interval-censored data, MCI-to-dementia conversion, model selection, random forest, survival data

DOI: 10.3233/JAD-240285

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 147-157, 2024

Authors: Ogbuagu, Chukwuanugo | Ogbuagu, Ekenechukwu | Emelumadu, Obiageli | Okereke, Uzoma | Okeke, Irene | Chigbo, Godswill | Javendal, Shireen | Miller, Bruce | Valcour, Victor | Allen, Isabel Elaine | Goode, Collette | Possin, Katherine L. | Uwakwe, Richard

Article Type: Research Article

Abstract: Background: Cognitive assessment is a key component of clinical evaluations for patients with dementia and Alzheimer’s disease in primary health care (PHC) settings. The need for well-validated, culturally appropriate, and easy-to-use assessments is especially urgent in low- and middle-income countries (LMICs) that are experiencing rapid growth in their older adult populations. Objective: To examine the feasibility and demographic determinants of performance for a tablet-based cognitive assessment tool (TabCAT) battery, which includes subtests for four cognitive domains, among older PHC patients in southeastNigeria. Methods: A cross-sectional mixed-method descriptive study evaluating the useability and performance of TabCAT. …Results: We enrolled 207 participants (mean age of 64.7±13.5 years; 52% with only primary, 41% secondary, and 7% tertiary education). Most (91%) who initiated the assessment were able to complete it, requiring 10–15 minutes to complete. More years of education was associated with better test scores across all tests (p  < 0.001). Living in a rural location was also associated with better performance (p  < 0.05). Male compared to female sex did not associate with performance on any of the tests (all ps > 0.05). Conclusions: Tablet-based cognitive assessment was feasible in rural and urban settings of Nigeria. Better performance on cognitive subtests linked to more education and residing in a rural area; however, sex did not predict performance. Digital cognitive assessment tools hold potential for widespread use in healthcare and educational contexts, particularly in regions with varying levels of urbanization and educational access. Show more

Keywords: Alzheimer’s disease, cognitive assessment, dementia, Nigeria, primary healthcare

DOI: 10.3233/JAD-240518

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 175-182, 2024

Authors: Zhang, Junyao | Zhang, Yinglin | Zhang, Yingying | Yao, Junyan

Article Type: Research Article

Abstract: Background: Our previous studies indicated that anesthesia/surgery could aggravate cognitive impairment and tau pathology in female 5XFAD transgenic (Tg) mice. However, it is unknown whether there are sex differences in the susceptibility of developing postoperative cognitive dysfunction in 5XFAD Tg mice. Objective: In this study, we aim to determine whether anesthesia/surgery can have different effects on female and male 5XFAD Tg mice, and to explore the underpinning mechanisms. Methods: The mice received abdominal surgery under isoflurane anesthesia. Morris water maze was used to assess the cognitive function. Hippocampal levels of p-tau (AT8), p-IRS1 (Ser612), IRS1, p-GSK3β …(Tyr216), and p-GSK3β (Ser9) at postoperative day 1 were evaluated by western blot assays. Results: Anesthesia/surgery exaggerated cognitive impairment and tau pathology in female, but not male 5XFAD Tg mice. The anesthesia/surgery led to elevated hippocampus protein levels of p-IRS1 (Ser612)/IRS1 ratio and p-GSK3β (Tyr216) and reduced hippocampus protein levels of p-GSK3β (Ser9) in female, but not male 5XFAD Tg mice. Conclusions: This study demonstrated that female 5XFAD Tg mice were more susceptible to anesthesia/surgery-induced cognitive deterioration and tau pathology aggravation, potentially due to female-specific brain insulin resistance. Show more

Keywords: Alzheimer’s disease, anesthesia/surgery, brain insulin resistance, cognitive dysfunction, sex difference, tau

DOI: 10.3233/JAD-231444

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 183-195, 2024

Authors: Cui, Xiaoyan | Wang, Junqiao | Tang, Xueting | Ding, Ding | Wu, Bei | Zhao, Qianhua | Wang, Jing

Article Type: Research Article

Abstract: Background: Young-onset dementia (YOD) refers to dementia occurring before the age of 65, with Alzheimer’s disease being the most common form, posing distinct challenges for spousal caregivers. Objective: This study aims to investigate the unique experiences of spousal caregivers of persons with YOD in China, where dementia-specific community care services and primary healthcare professionals are relatively lacking, in order to inform the tailored support services development. Methods: This qualitative-design study utilized semi-structured interviews with 11 spousal caregivers of persons with YOD dwelling in the community. Traditional content analysis was employed to analyze the interview data. …Results: Limited dementia-specific healthcare professionals and low public awareness made diagnosing and accepting YOD a prolonged and challenging journey. Spousal caregivers faced skepticism when seeking diagnosis, exacerbating their burden and emotional stress. Disparities in healthcare professionals and insufficient collaboration between institutions worsened the situation. YOD significantly impacted family dynamics and led to changes in emotional communication within the family. The stigma surrounding YOD raised concerns among spousal caregivers about their children’s future in marriage and career, emphasizing genetic risks. Conclusions: In settings where dementia-specific community care services and primary healthcare professionals are limited and unevenly distributed, integrating support services at both the primary and community levels is crucial for families dealing with YOD in the community. Additionally, raising public awareness about YOD can foster a more understanding and supportive environment, addressing challenges related to stigma faced by affected families, contributing to increased investment in supporting resources, and encouraging individuals to seek help early on. Show more

Keywords: Alzheimer’s disease, caregiving experiences, challenges, spousal caregiver, young-onset dementia

DOI: 10.3233/JAD-240249

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 197-209, 2024

Authors: Rustamzadeh, Auob | Tafakhori, Abbas | Ariaei, Armin | Heydari, Mahdi | Shah-abadi, Mehran Ebrahimi | Seif, Farhad

Article Type: Research Article

Abstract: Background: Laminopathy is a pathological manifestation observed in Alzheimer’s disease (AD), leading to neuronal apoptosis. Objective: Our objective was to assess inhibitors of enzymes involved in laminopathy. Methods: The mRNA expression of the cathepsins L and B, caspases 3 and 6, lamins b1 and b2, granzymes A and B, and lamins A and C were extracted and analyzed from GSE5281 and GSE28146 datasets. A total of 145 ligands were selected for molecular docking. Subsequently, 10 ns and 100 ns atomistic molecular dynamics (MD) and Martini 3 were performed with NAMD for two selected ligands (PubChem id: 608841 and …ChEMBL id: 550872). Results: The mRNA expression level highlighted caspase 6 and lamin A/C upregulation in the hippocampus of the AD samples, in contrast to cathepsin B, lamin b2, and caspase 3. Moreover, there was a strong correlation between the expression level of cathepsin B, lamin A/C, and caspase 6 in the AD group. The MD results suggested molecule with ChEMBL id of 550872 had higher free binding energy, while in longer simulation the molecule with PubChem id of 608841 was suggested to be more stable in complex with the receptor. Conclusions: Our findings suggest that lamins A/C, cathepsins B/L, caspase 6, and lamin B2 are associated with laminopathy as potential factors contributing to apoptosis in AD. We propose that simultaneous inhibition of caspases 6 and cathepsins L may decrease the rate of apoptosis triggered by lamin degradation. Nevertheless, further studies are required to confirm these observations due to the lack of in vivo findings. Show more

Keywords: Alzheimer’s disease, laminopathy, molecular dynamics, transcriptome

DOI: 10.3233/JAD-240413

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 211-221, 2024

Authors: Engedal, Knut | Benth, Jūratė Šaltytė | Wagle, Jørgen | Gjøra, Linda | Selbæk, Geir | Persson, Karin

Article Type: Research Article

Abstract: Background: The Clock Drawing Test (CDT) is used to screen for Alzheimer’s disease and other dementia disorders. Normative scores on the version from the Montreal Cognitive Assessment (MoCA) do not exist in the Nordic countries. Objective: To examine the normative scores of the CDT among adults aged 70 years and older. Methods: We included 4,023 cognitively healthy persons aged 70–97 years from a population survey in Norway. They were examined with the CDT, which has a total score between zero and three. A multiple multinominal regression model was applied with a CDT score as the dependent …categorical variable and estimated the probabilities of scoring a particular score, stratified by age, sex, and education. These probabilities correspond to an expected proportion of the normative population scoring at, or below a given percentile. Results: None scored zero, 2.1% scored one, 14.9% scored two, and 83% scored three. Higher age, female sex and fewer years of schooling were associated with poorer performance. Scores of zero and one deviated from the normative score regardless of age, sex and education. A score of two was within the norm for a female older than 81 and a male older than 85. Conclusions: The majority (83%) of people 70 years and older had a score of three on the CDT. Lower age, male sex, and higher education were associated with a better performance. Scores of zero and one were below the normative score. Except for the very old, a score of two was also well below the normative score. Show more

Keywords: Alzheimer’s disease, Clock Drawing Test, cognitive impairment, dementia, normative score

DOI: 10.3233/JAD-231331

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 223-234, 2024

Authors: Fan, Meixiang | Li, Qingfeng | Yang, Tingting | Yang, Yinghua | Chen, Zhihua | Xuan, Guo | Ruan, Ye | Sun, Shuangyuan | Wang, Meng | Chen, Xiaoli | Huang, Yanyan | Yang, Zhi | Wang, Ying

Article Type: Research Article

Abstract: Background: Previous trials have indicated that multimodal training could improve cognitive functions and moods in individuals with mild cognitive impairment (MCI). However, evidence was mainly obtained from studies in high-income countries. Objective: This trial aims to investigate the efficacy, safety, and potential mechanism of a multimodal intervention on cognitive function in individuals with MCI living in a community. Methods: In this single-blind, randomized controlled trial, 120 participants with MCI were randomly assigned to either the intervention group or the control group. The intervention group received the multimodal intervention, while the control group received regular health education. …Neuropsychological tests and magnetic resonance imaging (MRI) were conducted at baseline and after the 12-week intervention. Results: Fifty-nine and fifty-seven participants respectively in the intervention and control groups completed the trial. The intervention group shown improvements in primary outcome, Mini-Mental State Exam (MMSE) total score (mean difference –0.96, 95% CI [–1.58, –0.34], p  = 0.003), and secondary outcomes: MMSE recall (–0.39, 95% CI [–0.71, –0.07], p  = 0.019), MMSE language (–0.26, 95% CI [–0.44, –0.07], p  = 0.007), Auditory Verbal Learning Test instantaneous memory (–3.30, 95% CI [–5.70, –0.89], p  = 0.008), Digit Symbol Substitution Test total score (–2.91, 95% CI [–5.67, –0.15], p  = 0.039), digit span forwards (–1.25, 95% CI [–1.93, –0.56], p  < 0.001), and Digit Span Test (–1.33, 95% CI [–2.33, –0.34], p  = 0.009) compared to the control group. Improvements were observed in structural and functional connectivity related to language, concentration, executive function, memory, and recall functioning via MRI in the intervention group. Conclusions: The multimodal intervention improved cognitive function in individuals with MCI in cognitive performance and neuroimaging. Show more

Keywords: Alzheimer’s disease, behavior therapy, clinical trial, cognitive dysfunction

DOI: 10.3233/JAD-231370

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 235-248, 2024

Authors: Avelar-Pereira, Bárbara | Phillips, Curran Michael | Hosseini, S. M. Hadi

Article Type: Research Article

Abstract: Background: Age represents the largest risk factor for Alzheimer’s disease (AD) but is typically treated as a covariate. Still, there are similarities between brain regions affected in AD and those showing accelerated decline in normal aging, suggesting that the distinction between the two might fall on a spectrum. Objective: Our goal was to identify regions showing accelerated atrophy across the brain and investigate whether these overlapped with regions involved in AD or where related to amyloid. Methods: We used a longitudinal sample of 137 healthy older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), who underwent …magnetic resonance imaging (MRI). In addition, a total of 79 participants also had longitudinal positron emission tomography (PET) data. We computed linear-mixed effects models for brain regions declining faster than the average to investigate variability in the rate of change. Results: 23 regions displayed a 0.5 standard deviation (SD) above average decline over 2 years. Of these, 52% overlapped with regions showing similar decline in a matched AD sample. Beyond this, the left precuneus, right superior frontal, transverse temporal, and superior temporal sulcus showed accelerated decline. Lastly, atrophy in the precuneus was associated with increased amyloid load. Conclusions: Accelerated decline in normal aging might contribute to the detection of early signs of AD among healthy individuals. Show more

Keywords: Accelerated atrophy, Alzheimer’s disease, amyloid acculumation, gray matter, normal aging

DOI: 10.3233/JAD-231458

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 249-258, 2024

Authors: Nataraj, Athira | Kala, Annu | Proskauer Pena, Stephanie Lissette | Jezek, Karel | Blahna, Karel

Article Type: Research Article

Abstract: Background: The hippocampal representation of space, formed by the collective activity of populations of place cells, is considered as a substrate of spatial memory. Alzheimer’s disease (AD), a widespread severe neurodegenerative condition of multifactorial origin, typically exhibits spatial memory deficits among its early clinical signs before more severe cognitive impacts develop. Objective: To investigate mechanisms of spatial memory impairment in a double transgenic rat model of AD. Methods: In this study, we utilized 9–12-month-old double-transgenic TgF344-AD rats and age-matched controls to analyze the spatial coding properties of CA1 place cells. We characterized the spatial memory representation, …assessed cells’ spatial information content and direction-specific activity, and compared their population coding in familiar and novel conditions. Results: Our findings revealed that TgF344-AD animals exhibited lower precision in coding, as evidenced by reduced spatial information and larger receptive zones. This impairment was evident in maps representing novel environments. While controls instantly encoded directional context during their initial exposure to a novel environment, transgenics struggled to incorporate this information into the newly developed hippocampal spatial representation. This resulted in impairment in orthogonalization of stored activity patterns, an important feature directly related to episodic memory encoding capacity. Conclusions: Overall, the results shed light on the nature of impairment at both the single-cell and population levels in the transgenic AD model. In addition to the observed spatial coding inaccuracy, the findings reveal a significantly impaired ability to adaptively modify and refine newly stored hippocampal memory patterns. Show more

Keywords: Alzheimer’s disease, place cell directionality, place field size, spatial memory, TgF344-AD rats

DOI: 10.3233/JAD-231386

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 259-276, 2024

Authors: Lastuka, Amy | Bliss, Elye | Breshock, Michael R. | Iannucci, Vincent C. | Sogge, William | Taylor, Kayla V. | Pedroza, Paola | Dieleman, Joseph L.

Article Type: Research Article

Abstract: Background: Dementia prevalence is expected to increase as populations grow and age. Therefore, additional resources will be needed to meet the global demand for care for Alzheimer’s disease and related dementias (ADRD). Objective: Estimate global and country-level health care spending attributable to ADRD and the cost of informal care for people living with ADRD. Methods: We gathered data from three systematic literature reviews and the Global Burden of Disease 2019 study. We used spatiotemporal Gaussian process regression to impute estimates for the many countries without underlying data. We projected future costs to 2050 based on past …trends in costs, diagnosis rates, and institutionalization rate. Results: We estimated that in 2019, the direct health care spending attributable to ADRD across 204 countries reached $260.6 billion (95% uncertainty interval [UI] 131.6–420.4) and the cost of informal ADRD care was $354.1 billion (95% UI 190.0–544.1). On average, informal care represents 57% (95% UI 38–75%) of the total cost of care. We estimated that direct health care spending attributable to ADRD will reach $1.6 trillion (95% UI 0.6–3.3) in 2050, or 9.4% (95% UI 3.9–19.6%) of projected health spending worldwide. We estimated the cost of informal care will reach $0.9 trillion (95% UI 0.3–1.7) in 2050. Conclusions: These cost estimates underscore the magnitude of resources needed to ensure sufficient resources for people living with ADRD and highlight the role that informal care plays in provision of their care. Incorporating informal care cost estimates is critical to capture the social cost of ADRD. Show more

Keywords: Alzheimer’s disease, dementia, health care costs, informal care

DOI: 10.3233/JAD-240163

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 277-292, 2024

Authors: Ilardi, Ciro Rosario | Menichelli, Alina | Michelutti, Marco | Cattaruzza, Tatiana | Federico, Giovanni | Salvatore, Marco | Iavarone, Alessandro | Manganotti, Paolo

Article Type: Research Article

Abstract: Background: In the era of disease-modifying therapies, empowering the clinical neuropsychologist’s toolkit for timely identification of mild cognitive impairment (MCI) is crucial. Objective: Here we examine the clinimetric properties of the Montreal Cognitive Assessment (MoCA) for the early diagnosis of MCI due to Alzheimer’s disease (MCI-AD). Methods: Data from 48 patients with MCI-AD and 47 healthy controls were retrospectively analyzed. Raw MoCA scores were corrected according to the conventional Nasreddine’s 1-point correction and demographic adjustments derived from three normative studies. Optimal cutoffs were determined while previously established cutoffs were diagnostically reevaluated. Results: The original …Nasreddine’s cutoff of 26 and normative cutoffs (non-parametric outer tolerance limit on the 5th percentile of demographically-adjusted score distributions) were overly imbalanced in terms of Sensitivity (Se) and Specificity (Sp). The optimal cutoff for Nasreddine’s adjustment showed adequate clinimetric properties (≤23.50, Se = 0.75, Sp = 0.70). However, the optimal cutoff for Santangelo’s adjustment (≤22.85, Se = 0.65, Sp = 0.87) proved to be the most effective for both screening and diagnostic purposes according to Larner’s metrics. The results of post-probability analyses revealed that an individual testing positive using Santangelo’s adjustment combined with a cutoff of 22.85 would have 84% post-test probability of receiving a diagnosis of MCI-AD (LR+ = 5.06). Conclusions: We found a common (mal)practice of bypassing the applicability of normative cutoffs in diagnosis-oriented clinical practice. In this study, we identified optimal cutoffs for MoCA to be allocated in secondary care settings for supporting MCI-AD diagnosis. Methodological and psychometric issues are discussed. Show more

Keywords: Alzheimer’s Disease, clinimetrics, cutoffs, diagnosis, Mild Cognitive Impairment, Montreal Cognitive Assessment

DOI: 10.3233/JAD-240339

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 293-308, 2024

Authors: Solingapuram Sai, Kiran Kumar | Erichsen, Jennifer M. | Gollapelli, Krishna K. | Krizan, Ivan | Miller, Mack | Bansode, Avinash | Jorgensen, Mathew J. | Register, Thomas | Cazzola, Charles | Gandhi, Reenal | Suman, Julie | Craft, Suzanne

Article Type: Research Article

Abstract: Background: Intranasal insulin (INI) is being explored as a treatment for Alzheimer’s disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes. Objective: To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system. Methods: To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68 Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68 Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain …regional activity and whole-body dosimetry following PET/CT scans. Results: We observed brain penetration of [68 Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68 Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68 Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq. Conclusions: The use of [68 Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68 Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68 Ga]Ga-NOTA-insulin administration in humans. Show more

Keywords: Alzheimer’s disease, insulin, intranasal administration, primates

DOI: 10.3233/JAD-240484

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 309-320, 2024

Authors: Lee, Tsz-lok | Chan, Agnes S.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease has become increasingly prevalent among the older population, leading to significant social and economic burdens. Transcranial photobiomodulation (tPBM) has shown promise as a cognitive intervention for enhancing cognitive efficiency in healthy older adults, and individuals with mild cognitive impairment and Alzheimer’s disease. However, determining the optimal tPBM dosage is crucial for ensuring effective and efficient intervention. Objective: This study aimed to compare the effects of different dosages in a single tPBM session on cognitive efficiency in healthy older adults. Methods: In this randomized controlled trial, 88 healthy older participants were assigned to either …a single dose (irradiance = 30 mW/cm2 , fluence = 10.8 J/cm2 ; n  = 44) or a double dose (irradiance = 30 mW/cm2 , fluence = 21.6 J/cm2 ; n  = 44) tPBM session. Cognitive efficiency was assessed using functional near-infrared spectroscopy during a visual working memory span task. Results: The single dose group exhibited significantly greater cognitive efficiency enhancement, indicated by a more pronounced reduction in oxygenated hemoglobin during a challenging task level (span level 9) (p  = 0.021, d = 0.50), and better working memory task performance (p  = 0.045, d = 0.31). Furthermore, participants with better visuospatial abilities demonstrated greater improvement after a single dose (r  = –0.42, p  = 0.004). In contrast, participants with varying cognitive function did not exhibit additional benefits from a double dose (r  = –0.22–0.15, p  = 0.16–0.95). Conclusions: These findings suggest that higher tPBM dosages may not necessarily result in superior cognitive improvement in older adults. Show more

Keywords: Alzheimer’s disease, cognitive aging, cognitive efficiency, cognitive intervention, functional near-infrared spectroscopy, photobiomodulation

DOI: 10.3233/JAD-240473

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 321-335, 2024

Authors: Li, Kuide | Mo, Dan | Yu, Qian | Feng, Rongjian | Li, Yamei

Article Type: Research Article

Abstract: Background: There are currently no uniform treatments for post-stroke comorbid cognitive impairment and depression (PSCCID). Objective: To verify whether repetitive transcranial magnetic stimulation (rTMS) can improve PSCCID symptoms and explore the underlying roles of resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Thirty PSCCID patients were randomized in a 1 : 1 ratio to receive 4 weeks of rTMS (intervention group) or sham rTMS (control group) over the left dorsolateral prefrontal cortex (DLPFC). rs-fMRI was acquired to analyze the functional plasticity of brain regions at baseline and immediately after the last intervention. Results: Cognition, depression status, and …neural electrophysiology were improved in both intervention and control groups after treatment (p  = 0.015–0.042), and the intervention group had more significant improvement than the control group. Analysis of functional connectivities (FCs) within the default mood network (DMN) showed that the connection strength of the left temporal pole/left parahippocampal cortex and right lateral temporal cortex/right retrosplenial cortex in the intervention group were enhanced compared with its pre-intervention and that in the control group after treatment (p  < 0.05), and the both FC values were positively correlated with MMSE scores (p  < 0.001). The intervention group had stronger FCs within the DMN compared with the control group after treatment, and some of the enhanced FCs were correlated with the P300 latency and amplitude. Conclusions: rTMS over the left DLPFC is an effective treatment for improving both cognitive impairment and depression among patients with PSCCID. The enhanced FCs within the DMN may serve as a compensatory functional recombination to promote clinical recovery. Show more

Keywords: Alzheimer’s disease, cognitive impairment, default mood network, depression, repetitive transcranial magnetic stimulation, stroke

DOI: 10.3233/JAD-240505

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 337-352, 2024

Authors: Neve, Anuja | Das, Bibha | Wojtowicz, Jakub | Huang, Zhiyue | Bullain, Szofia | Watkin, Michelle | Lott, Dominik | Bittner, Tobias | Delmar, Paul | Klein, Gregory | Hofmann, Carsten | Kerchner, Geoffrey A. | Smith, Janice | Baudler, Monika | Fontoura, Paulo | Doody, Rachelle S.

Article Type: Research Article

Abstract: Background: Gantenerumab is an anti-amyloid-β immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in Marguerite RoAD (MR; NCT02051608), a Phase III, double-blind (DB), placebo-controlled study in participants with mild Alzheimer’s disease (AD) dementia. Following a preplanned futility analysis of the SCarlet RoAD study (NCT01224106), MR was converted into an open-label extension (OLE). Objective: The DB study aimed to assess the efficacy of gantenerumab compared with placebo from baseline to Week 104 in participants with mild AD dementia. Following conversion to an OLE, this objective became exploratory, …as the OLE assessed the long-term safety and tolerability of SC gantenerumab at doses of up to 1,200 mg every 4 weeks (Q4W) in OLE participants. Methods: Eligible DB study participants were offered the opportunity to receive gantenerumab up-titrated to 1,200 mg Q4W. Safety and tolerability were assessed using magnetic resonance imaging (MRI), physical and neurologic examinations, and adverse event monitoring. Results: Overall, 225 participants were rolled over from the DB part of MR and received ≥1 gantenerumab dose in the OLE. The median treatment duration was 123 weeks. Fifty-nine (26.2%) and 41 (18.2%) participants had amyloid-related imaging abnormality (ARIA)-edema and ARIA-hemorrhage MRI findings, respectively. ARIA findings were manageable with MRI monitoring and dose intervention; most were asymptomatic. There were no unexpected safety findings. Conclusions: SC gantenerumab at doses of up to 1,200 mg Q4W were well tolerated in participants with mild AD dementia. Show more

Keywords: Alzheimer’s disease, clinical efficacy, clinical trial, gantenerumab, safety

DOI: 10.3233/JAD-240221

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 353-367, 2024

Authors: Cardoso, Sandra | Guerreiro, Manuela | Montalvo, Alexandre | Silva, Dina | Alves, Luísa | de Mendonça, Alexandre

Article Type: Research Article

Abstract: Background: The concept of amnestic mild cognitive impairment (aMCI) was developed to identify patients at an initial stage of Alzheimer’s disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology or neuronal injury. Objective: To know the natural history of amyloid-negative and neurodegeneration-negative patients with aMCI, namely to ascertain: 1) whether these patients remain cognitively stable or they present a slow decline in neuropsychological tests; 2) whether the memory complaints subside with the apparently benign clinical course of the disorder or if they persist along the time. Methods: Patients who fulfilled criteria …for aMCI with no biomarkers of amyloid pathology or neuronal injury were selected from a large cohort of non-demented patients with cognitive complaints, and were followed with clinical and neuropsychological assessments. Results: Twenty-one amyloid-negative and neurodegeneration-negative aMCI patients were followed for 7.1±3.7 years. At the baseline they had more pronounced deficits in verbal learning (California Verbal Learning Test) and were also impaired in Word Recall and Logical Memory. However, they did not decline in any cognitive test during follow-up. The patients maintained a high level of subjective memory complaints from baseline (9.7±4.1) to the follow-up visit (9.2±4.1, a non-significant difference), in spite of a statistically significant decrease in the depressive symptoms, with Geriatric Depression Scale (15 items) score 4.9±2.8 at baseline and 3.2±1.8 at the follow-up visit. Conclusions: Amyloid-negative, neurodegeneration-negative aMCI is a chronic clinical condition characterized by the long-term persistence of cognitive deficits and distressing memory complaints. Adequate strategies to treat this condition are needed. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, amyloid-β, amyloid-negative, biomarkers, dementia, follow-up

DOI: 10.3233/JAD-240621

Citation: Journal of Alzheimer's Disease, vol. 101, no. 1, pp. 369-377, 2024