bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of tetrahydrocannabinol and melatonin combination on suicide ideation and behavior in dementia due to Alzheimer’s disease
Authors: Delgado‐Murillo Laura , Gutierrez Evelyn , Sanchez Laura Tatiana , Arbelaez María Juanita , Tangarife Maria Alejandra , Rodriguez‐Soacha Diego , Shahnawaz Saadia S , Ghazaryan Varduhi , Naranjo Maria Paula , Venegas Margarita , Silva‐García David , Pujals Karen Y , De Jesus William Julio , Grimaldi Claudia , Lanctôt Krista L. , Hong L Elliot , Mukunda Ram 
Published: December 2023

AbstractBackgroundSuicide ideation in young adults increases with regular use of marijuana. Separately, prevalence of suicide and dementia also increases with age, and Alzheimer’s disease (AD) is associated with a moderate risk of suicide. The Columbia‐Suicide Severity Scale (C‐SSRS) has been used since the FDA guidance in 2012, however, it has not been validated. Studies show its effectiveness in mild to moderate dementia, but not in severe dementia. Here, we present preliminary data on the application of C‐SSRS in a Phase 1 trial on AD patients using IGC‐AD1, a combination of tetrahydrocannabinol (THC) and melatonin (IGC‐AD1).MethodTwelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5 ± 5.5yrs, 69.2% women) participated in a three Cohort Phase‐1, MAD, safety, and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts 2 and 3, one ml BID and TID were administered respectively with a minimum of 4‐days washout between Cohorts. Daily, solicited, and non‐solicited adverse events (AEs) were monitored along with vital signs.For all three Cohorts the C‐SSRS was administered at baseline and again on days 5,10, EOT and EOT+2 by a neuropsychologist. In addition, suicidal ideation was included as a solicited adverse event (AE) that was reported daily.ResultIn 420 man‐days (10 patients on active * 14 days * 3‐Cohorts) of dosing there was one day on which a participant on active medication self‐reported suicidal ideation as part of the solicited AEs. It self‐resolved the next day. All 150 administrations of C‐SSRS to the participants on active medication, across all three Cohorts, showed no suicide ideation or behavior. Likewise, across 30 administrations in the placebo group there were no suicide ideations or behaviors. No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were reported.ConclusionTHC and melatonin in IGC‐AD1 did not increase the risk of developing suicidal ideation or behavior as assessed by the C‐SSRS in the mild to moderate AD trial population. The preliminary results also show that IGC‐AD1 was well tolerated and safe.
Behavioral functional networks underlying the effect of Alzheimer’s pathology on cognition
Authors: Ziontz Jacob , Harrison Theresa M. , Jagust William J. 
Published: December 2023

AbstractBackgroundTau pathology is associated with impaired cognitive function in both aging and Alzheimer’s disease (AD), but the mechanisms by which tau and cognition are linked remain unclear. We hypothesized that the integrity of behaviorally‐defined functional brain networks would help explain the relationship between tau and cognitive performance.MethodResting state fMRI, tau PET, and Ab PET were collected in two independent cohorts: 120 cognitively normal older adults from the Berkeley Aging Cohort Study (BACS; 77.6 ± 6.4 yrs), and 174 cognitively normal and MCI individuals from ADNI3 (72.8 ± 8.3 yrs). For each cohort, functional connectivity (FC) for each ROI‐ROI pair of a 246‐region atlas was computed, and LASSO+BIC regression of these values against episodic memory (EM) and executive function (EF) composite measures was used to define a sparse subset of connections positively associated with each cognitive measure. Overall network strength was computed as the sum of FC values for all selected ROI‐ROI pairs.ResultEM and EF networks were identified within each cohort, with Dice similarity coefficients indicating greater overlap of network regions within cohorts (BACS networks: 0.43; ADNI: 0.33) than within cognitive measures between cohorts (EM networks: 0.25; EF: 0.23; Figure 1). Adjusting for age and sex, lower EM network strength was associated with greater meta‐temporal ROI tau in both BACS (b = ‐4.05, p = .014) and ADNI (b = ‐2.20, p <.001), whereas lower EF network strength was related to meta‐ROI tau in ADNI only (b = ‐1.80, p <.001; Figure 2). In addition, causal mediation analysis revealed that the effect of meta‐ROI tau on EM performance was mediated by EM network strength in both BACS (p = .017) and ADNI (p = .002), but EF network strength was a significant mediator in ADNI only (p <.001; Figure 3).ConclusionGreater AD pathology is associated with reduced integrity of EM‐related networks in older adults, a relationship that may also extend to EF‐related networks as individuals progress from cognitively normal to MCI. Given that network strength was observed to mediate the relationship between tau pathology and cognition, behavioral brain networks may be a key mechanism in the effect of neuropathology on cognitive function in aging and AD.
Diffusion MRI free water in hippocampal subfields CA3 and CA1 tracks progression in prodromal and overt synucleinopathy
Authors: Huddleston Daniel , Langley Jason , Chen Xiangchuan , Tucker Kelsey , Littrell Kevin , Maan Saad , Hyland Sierra , Bliwise Donald , Hu Xiaoping 
Published: December 2023

AbstractBackgroundPostmortem study of the hippocampal subfields in the Lewy body dementias has revealed selective involvement of CA3 with synuclein pathology and CA1 with amyloid and tau, i.e., Alzheimer’s disease (AD) co‐pathology (Coughlin et al., 2020, PMID:32892355). However, new neuroimaging methods are needed to study the hippocampal subfields in vivo in synucleinopathies. Diffusion MRI free water (FW) measurement detects increased hippocampal FW in AD (Ofori et al., 2019, PMID:31470214). However, typical diffusion MRI protocols have voxels ≥ 2 mm3 making hippocampal subfield imaging infeasible due to volume averaging effects. To address this, we developed a high‐resolution diffusion MRI protocol capable of imaging the hippocampal subfields. We applied this approach to study a prodromal synucleinopathy group – idiopathic REM sleep behavior disorder (iRBD), as well as PD with normal cognition (PD‐NC), PD with cognitive impairment (PD‐CI), and dementia with Lewy bodies (DLB).MethodParticipants with PD‐NC, PD‐CI, DLB, and polysomnographically confirmed iRBD were recruited at Emory University. T1 MPRAGE (0.8mm3 voxels) and high‐resolution diffusion MRI (b = 0, 500mm2/sec; 30 diffusion directions; 1.1mm3 voxels) data were acquired with a Siemens 3T Prisma‐fit system. FreeSurfer v7 was used to segment hippocampal subfields. FW was measured as described in Ofori, et al (2017, PMID:28714593). Groups were compared using ANCOVA followed by post‐hoc tests, and clinical and MRI features were correlated.Result
Table 1 shows group demographic and clinical characteristics. A progressive increase in CA3 and CA1 FW was observed from iRBD to PD‐NC to PD‐CI and DLB, and the ANCOVA model, controlling for age, found a statistically significant difference between groups for CA3 FW (Figure 1). Figure 2 shows statistically significant negative correlations between MoCA and hippocampal FW measures and between years of education and FW in CA3 and CA1.ConclusionCA3 and CA1 FW are significantly increased in advanced synucleinopathy (DLB, PD‐CI) as compared to iRBD, and PD‐NC has intermediate values. Strong negative correlations between CA3 and CA1 FW and cognition further indicate that these measures may track disease progression. The negative correlations between CA3 and CA1 FW and education also suggest that these measures may be biological correlates of cognitive reserve.
Transient CSF1R Inhibition in the Early Stage of AD Retains Homeostatic Microglia with Reduced Inflammasomes and Increased autophagy in the 5XFAD Model
Authors: Kodali Maheedhar , Gonzalez Jenny J , Oake Chris , Huard Charles , Somayaji Yogish , Shuai Bing , Madhu Leelavathi N , Attaluri Sahithi , Rao Shama , Shankar Goutham , Panda Prashanta K , Hering Catherine , Babu Roshni S , Shetty Ashok K 
Published: December 2023

AbstractBackgroundChronic neuroinflammation is one of the most conspicuous features of Alzheimer’s disease (AD). While microglia play a vital role in phagocytosing amyloid beta (Aβ) and restraining plaque extension, disease‐associated microglia are known to perpetuate neuroinflammation. Previous studies have shown that ∼80% microglia elimination through a month‐long colony‐stimulating factor 1 receptor (CSF1R) inhibition in the advanced stage of AD in 5X Familial AD (5XFAD) mice does not reduce Aβ levels or plaques but restrains synapse loss and neurodegeneration. On the other hand, prolonged CSF1R inhibition has been shown to prevent parenchymal plaque development. However, the immediate effects of transient CSF1R inhibition in the early stage of AD on residual microglial morphology and their metabolic fitness are unknown.MethodWe investigated the impact of transient CSF1R inhibition in three‐month‐old 5XFAD mice, a stage at which neuroinflammation has commenced, but Aβ plaques were minimal. Microglia from the hippocampus and the somatosensory cortex (SSC) of 5XFAD mice receiving a diet containing either the CSF1R inhibitor PLX5622 or a standard diet for ten days were examined for morphology, markers of NOD‐, LRR‐, and pyrin domain‐containing protein 3 (NLRP3) inflammasome complex, autophagy, and mechanistic target of rapamycin (mTOR) signaling.ResultTen days of CSF1R inhibition resulted in 67‐70% depletion of microglia in the hippocampus and SSC. The residual microglia displayed a noninflammatory phenotype, typified by highly branched and ramified processes, reduced incidence of NLRP3 inflammasome complexes, and increased autophagy. Interestingly, Aβ plaque load was reduced, and mTOR signaling was unaltered in microglia but reduced in neurons. However, transient CSF1R inhibition did not impact astrocyte hypertrophy or neurogenesis in the hippocampus.ConclusionThe results showed that transient CSF1R inhibition in the early stage of AD promotes the retention of homeostatic microglia with reduced inflammasomes and better metabolic fitness but with no changes in mTOR signaling, which can restrain the perpetuation of neuroinflammation and improve phagocytosis of Aβ by microglia.
Network propagation unveils molecular mechanisms modulated in Alzheimer’s Disease patients treated by the complex plasma fraction GRF6019
Authors: File Balint , Nanasi Tibor , Lohr Scott , Braithwaite Steven P , Lehallier Benoit 
Published: December 2023

AbstractBackgroundOur pre‐clinical work provided evidence of the interest of plasma fraction treatment to reverse age‐related cognitive decline. One of the most potent plasma fractions, GRF6019 was tested on patients with Alzheimer’s disease (AD). GRF6019 was safe and well tolerated, and patients experienced no cognitive decline and minimal functional decline. However, understanding these responses requires large‐scale mapping of the underlying molecular mechanisms. Recent affinity‐based approaches can measure levels of thousands of proteins in plasma but the increased signal‐to‐noise ratio and the large‐scale analysis of the proteomics changes require sophisticated bioinformatic techniques. To this end, we applied network propagation methods and combined protein‐protein interaction (PPI) networks, known AD‐associated proteins and GRF6019 induced protein changes to shed the light on the molecular mechanisms underlying patients’ responses to GRF6019 treatment.MethodPhase 2 clinical trials with repeated infusions of the plasma fraction GRF6019 were conducted in patients with AD (GRF6019‐201 n = 40 and GRF6019‐202 n = 26). Proteomic measurements from 136 plasma samples across three timepoints were performed by SomaLogic and Olink platforms. GRF6019‐induced proteomics changes were expressed by a Modulation Score (MS) for each protein. This MS captures the amplitude of the proteomics changes and the consistency of these changes within and between trials. Network propagation modeled the spread of MS on the PPI network. The network propagation algorithm we applied was the fusion of Hierarchical HotNet (permutation part) and NetCore (coreness normalization part). The algorithm highlighted the perturbed proteins which are close in the PPI network topology to proteins with high MS.ResultHighly perturbed proteins were more strongly associated with AD and other age‐related diseases (e.g.: AMD, Ischemic stroke) than proteins with high MS. Several pathways involved in AD were found to be associated to the perturbed proteins, such as complement and monocyte activation, or regulation of neurogenesis. Furthermore, the high overlap between proteins perturbed by GRF6019 and known AD‐associated proteins indicates the importance of indirect links between the GRF6019 treatment and AD.ConclusionNetwork propagation procedure highlights the importance of interactome‐based analysis in understanding complex plasma proteomics signals. These results suggest that the treatment of AD patients with a complex plasma fraction modulates AD‐related biological pathways.
Topographical pattern of blood‐brain barrier impairment in preclinical and clinical Alzheimer’s disease
Authors: Yi Dahyun , Byun Min Soo , Park Joon Sik , Byeon Gihwan , Ahn Hyejin , Jung Gijung , Kang Koung Mi , Sohn Chul‐Ho , Park Jaeseok , Lee Dong Young 
Published: December 2023

AbstractBackgroundWhile blood‐brain barrier (BBB) damage in some brain regions has been suggested in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI), the topographical pattern of BBB impairment associated with AD process in whole brain level is still poorly understood. Using high‐resolution 3‐dimensional (3D) dynamic contrast‐enhanced (DCE) scans of BBB permeability (K
trans) for the whole brain, we aimed to reveal topographical pattern of BBB impairment related to Alzheimer’s disease (AD) including preclinical as well as clinically impaired state.MethodNinety‐one participants were included in the study [45 cognitively normal (CN) older adults, 24 individuals with mild cognitive impairment (MCI), and 22 patients with AD dementia]. Comprehensive clinical and neuropsychological assessments were administered to all participants. High‐resolution DCE‐ as well as T1‐weighted‐MRI scans were obtained in addition to amyloid‐PET scans. Amyloid‐beta (Ab) positivity was obtained using previously established cut‐offs. Preprocessing of K
trans maps incorporated FreeSurfer‐based (v6.0) segmentation to ensure exclusion of the voxels within cerebrospinal fluid (CSF) spaces. Voxel‐wise analyses were conducted using SPM12 implemented in MATLAB 2018b.ResultSubtle BBB impairment, as measured by K
trans map images based on high‐resolution 3D DCE‐MRI, was observed at multiple brain regions even in preclinical AD (i.e., Ab‐positive CN) as well as AD with cognitive impairment (i.e., Ab‐positive MCI and AD). The brain regions with impaired K
trans closely corresponded to the AD‐signature regions (Figure). Compared to Ab‐negative CN, Ab‐positive CN showed increased breakdown of BBB in the precuneus, posterior‐cingulate cortex, and medial temporal lobe. Moreover, compared to Ab‐negative CN, Ab‐positive MCI and AD patients showed increased breakdown of BBB in more diffuse regions including bilateral frontal, parietal and inferior temporal areas. In contrast, when using low‐resolution BBB images for the same participants, BBB damage was not detected in preclinical AD and observed at only limited brain regions in AD with cognitive impairment.ConclusionWe demonstrated topographical pattern of BBB impairment associated with preclinical AD as well as AD with cognitive impairment through technically advanced high‐resolution DCE‐MRI. The findings suggest that subtle BBB changes detectable from high‐resolution DCE‐MRI has potential as a biomarkers for detection and monitoring of BBB impairment in whole AD continuum.
Risk of motor vehicle collisions and culpability among older drivers using cannabis: a meta‐analysis
Authors: Chinna‐Meyyappan Arun , Wang Janet Hui Jue , Bawa Kritleen Kaur , Ellazar Edward A , Norris‐Roozman Emilie , Naglie Gary , Herrmann Nathan , Charlton Judith , Koppel Sjaan , Castel Saulo , Lanctôt Krista L. , Rapoport Mark J. 
Published: December 2023

AbstractBackgroundWhile the effects of cannabis use on driving have been established in younger populations, limited studies have investigated this association among older adults, who represent the fastest growing segment of drivers globally.MethodWe conducted a systematic review and meta‐analysis to evaluate the effect of THC exposure on (1) risk of motor vehicle collisions (MVC) and (2) risk of culpability (being responsible for the collision), among adults 50 years and older. Three reviewers screened 7,022 studies identified through MEDLINE, EMBASE, CENTRAL, and PsycINFO and published between inception and 2021. Odds Ratios (OR) were calculated with a random‐effects model using the Mantel‐Haenszel method in Review Manager 5.4.1. Heterogeneity was assessed using I2. An adapted version of the National Heart, Lung, and Blood Institute quality assessment tool was used to assess the quality of each study.Result7 cross‐sectional studies were included. Three studies were rated ‘Good’ quality, one rated ‘Fair’, and three rated ‘Poor’. Three of the included studies evaluated culpability (NTHC+ = 239 NTHC‐ = 4609) while four evaluated MVC risk (NTHC+ = 158, NTHC‐ = 6152). We found that the pooled risk of MVC was not significantly different between older drivers exposed to THC and those who were not (OR, 95% CI 1.15 [0.40, 3.31]; I2 = 72%). In the studies assessing driver culpability, THC exposure was not significantly associated with an increased risk of being culpable for MVC among adults over the age of 50 (OR, 95% CI 1.24 [0.95, 1.61]; I2 = 0%). A visual inspection of the funnel plots did not indicate any publication bias.ConclusionOur review found that THC exposure was not associated with MVC involvement nor with culpability. However, it would be an oversimplification to conclude that cannabis use does not pose a safety risk to older drivers. Rather, our results may reflect several methodological limitations of the studies included in this review. Due to the increasing prevalence of cannabis use worldwide, we are optimistic that future research will be able to address this research question using more objective methodologies.
Tau PET: utility as a biomarker for chronic traumatic encephalopathy
Authors: Krishnadas Natasha , Dore Vincent , Lamb Fiona , Guzman Rodney , Ponsford Jennie L , Hicks Amelia J , Williams Robert , Feizpour Azadeh , Villemagne Victor L , Rowe Christopher C 
Published: December 2023

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by tau deposition in the depths of the sulci associated with exposure to repetitive head impacts (RHI). It is a post‐mortem diagnosis. We previously reported a frontotemporal predominant tau 18F‐MK6240 PET pattern resembling the distribution of CTE in a retired Australian Rules Football player in the context of a moderate amyloid‐beta plaque burden.1 This study aimed to investigate the utility of 18F‐MK6240 PET as a potential biomarker for CTE in contact sports players with exposure to RHI (sRHI).MethodsRHI (n = 33) and age‐matched healthy controls (HC) (n = 32) completed amyloid (18F‐NAV4694) and tau (18F‐MK6240) PET scans. Amyloid PET was quantified in Centiloids. 18F‐MK240 standardized uptake value ratios (SUVRs) were generated for the dorsolateral prefrontal cortex and composite regions of interest (ROI) (frontal; mesial temporal; temporoparietal).ResultFor sRHI, the primary contact sport was Australian Rules Football (n = 17), boxing/kickboxing/martial arts (n = 11), rugby (n = 4) and soccer (n = 1), with 36.4% participating at a professional level. sRHI had a mean age of 54.2 (±9.2) (vs HC 53.0±9.5, p = 0.61), and 94% were male (vs HC 78%, p = 0.08). sRHI did not differ from HC in years of education (p = 0.46) but had more impaired MMSE (28.1±1.9 vs 29.3±0.8, p = 0.006, d = ‐0.80) and Clinical Dementia Rating scores (0.21±0.3 vs 0±0, p<0.001, d = 1.25). sRHI and HC did not differ in mean Centiloid values (2.9±8.4 vs 3.0±8.2). sRHI and HC did not differ in 18F‐MK6240 SUVR in the regions examined, and no differences were observed between professional and amateur sRHI.ConclusionContact sports players with exposure to repetitive head impacts did not differ from age‐matched healthy controls on 18F‐MK6240 SUVR in frontal, mesial temporal, and temporoparietal brain regions. Study limitations include the small sample size, heterogeneity in sports type and highest level of participation, and participants with relatively mild cognitive and functional impairments. Additionally, while 18F‐MK6240 has high affinity for 3R/4R tau in Alzheimer’s disease, its affinity in CTE, particularly important at early stages, remains unclear.
References
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1 Krishnadas N et al. Case report: 18F‐MK6240 tau positron emission tomography pattern resembling chronic traumatic encephalopathy in a retired Australian Rules Football player. https://doi.org/10.3389/fneu.2020.598980.
Handle with care: frailty complicates cognitive outcomes in older adults with delirium
Authors: Avelino‐Silva Thiago J , Garcez Flávia B 
Published: December 2023

AbstractBackgroundDelirium has been associated with long‐term cognitive impairment and dementia (1), and frailty is a known risk factor for incident dementia in older adults (2). However, it remains unclear whether delirium and frailty synergistically affect cognitive decline. We investigated whether frailty modifies the association between delirium and post‐discharge dementia in older adults.MethodsWe completed a cohort study including acutely ill older adults admitted to a tertiary university hospital (2010‐2016). Our inclusion criteria were: age ≥60 years; no preexisting cognitive decline; ≥12 months of follow‐up after discharge. Preexisting cognitive decline was identified using clinical history, CDR‐SB, and IQCODE‐16. Delirium was defined using the Short‐CAM. Frailty was defined using the FRAIL scale and the Frailty Index. Our primary outcome was the incidence of post‐discharge dementia, identified in follow‐up medical records. We investigated the association between delirium and post‐discharge dementia using competing‐risks regression models. We then completed interaction analyses exploring the effect of frailty on the association between delirium and post‐discharge dementia.ResultsWe included 309 participants (mean age = 78 years; female = 60%). We detected delirium in 66 (21%) hospitalizations and incident dementia in 59 (19%). Overall, 16% of the patients were classified by FRAIL as robust, 55% as prefrail, and 29% as frail. After multivariable analysis, we found that delirium was independently associated with incident dementia, but the association was significantly modified by frailty (p = 0.009) (Figure 1). The adjusted sub‐hazard ratio (SHR) in non‐frail participants was 1.14 (95%CI = 0.53‐2.44) and 3.80 (95%CI = 1.80‐8.05) in frail participants Tables 1‐2).ConclusionFrailty was a significant modifier of the association between delirium and post‐discharge dementia in this population. Research on frailty interventions should measure delirium incidence and long‐term cognitive decline to explore their potential impact on these outcomes.
References:1. Garcez FB, Apolinario D, Campora F, Curiati JAE, Jacob‐Filho W, Avelino‐Silva TJ. Delirium and post‐discharge dementia: results from a cohort of older adults without baseline cognitive impairment. Age Ageing. 2019;48(6):845‐851. https://doi.org/10.1093/ageing/afz107
2. Gray SL, Anderson ML, Hubbard RA, et al. Frailty and incident dementia. J Gerontol A Biol Sci Med Sci. 2013;68(9):1083‐1090. https://doi.org/10.1093/gerona/glt013