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

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