bluuebunny/crossref_metadata_2025 huggingface dataset:
Prescription profile of Alzheimer’s disease medications in the public health system in Southern Brazil
Authors: De Marco Maísa , Brandi Ana Laura , Krug Bárbara , Camozzato Analuiza , Picon Paulo Dornelles , Chaves Marcia L Fagundes , Castilhos Raphael Machado
Published: December 2023

Background

Alzheimer’s disease (AD) accounts for 60‐70% of cases of dementia, and is characterized by progressive decline in cognition and functionality. Pharmacological treatment is fundamentally symptomatic, and consist mainly of three acetylcholinesterase (IChE) inhibitors (donepezil, galantamine and rivastigmine) and one N‐methyl‐D‐aspartate (NMDA) receptor, memantine. Although these drugs are freely available in the public health system in Brazil, there may be barriers to accessing them. We aim to evaluate the profile of prescription of AD medication in the public health system in the state of Rio Grande do Sul (RS), Southern Brazil.

Methods

We analyzed all AD medications requested in the state of RS during October/2021 in the public health system. Sociodemographic, Mini Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale data were collected. We described the variables as median (interquartile range ‐ IQR) or frequencies. We also performed a spatial autocorrelation analysis of the medication prescribed in the RS municipalities. All analyses were performed in R.

Results

The total of 2,382 AD patients were using any AD medication. Most were female (65.6%), had elementary education (71.7%) and a median age of 79 (73‐84) years. The patients' MMSE median was 15 [12‐18] and most had a CDR = 2 (55.2%, 1133). The most prescribed medication was donepezil, 42.6% (1014), alone or in combination with memantine (Table 1). The distribution of the variable patient/100,000/municipality was clustered, with Moran’s I of 0.17562 (p<0.001) (Figure 1).

Conclusions

Most patients using AD medications in the public health system had moderate dementia. The distribution pattern of these medications in the RS state was uneven. The identification of factors related to these patterns may provide valuable information about the barriers to the access to AD treatment in the state of RS.
The Validity of the Thai Electronic Version of the Montreal Cognitive Assessment (MoCA)
Authors: Hemrungrojn Solaphat , Amrapala Arisara , Kasemsantitham Arp‐Arpa , Dithanat Praphada , Lapanan Kulvara , Chaiyasurayakan Kanokwan , Assawatinna Ratiya , Phutrakool Phanupong , Punyabukkana Proadpran , Nupairoj Natawut ,   Cognitive fitness and technology in biopsychiatry research unit
Published: December 2023

Electronic cognitive assessment tools are essential in screening and managing patients’ disease progression in clinical practices. Neurocognitive disorders, particularly mild cognitive impairment (MCI) and Alzheimer’s Dementia (AD), can be assessed using the Montreal Cognitive Assessment (MoCA) [1, 2]. A digital version of the MoCA could help reduce the burden on healthcare providers, increase accessibility, and maximize its utility, especially in countries that lack medical staff such as Thailand. This pilot study aimed to establish the concurrent validity between the electronic version of the MoCA‐Thai (eMoCA‐Thai), developed by the authors of this paper, to the original paper‐and‐pencil version (MoCA‐Thai) in adults who are cognitively normal (CN), have MCI, and have AD. 54 adults between the ages of 60 to 90 attending a dementia clinic were administered both the eMoCA‐Thai and the standard MoCA‐Thai one week apart. The primary outcome measures include the total scores and all subscale scores of the two test versions. Correlations and differences between scores were analyzed using concordance correlation coefficients (CCC) and various parametric t‐tests. Results show that there is high correlation for total MoCA scores with a CCC of 0.919 and a mean difference of ‐0.204 (‐6.311, 5.904). All the cognitive subdomain scores had moderate to high CCC of more than 0.4. The differences in average total score (22.81±7.49 for the MoCA‐Thai and 23.02±7.99 for the eMoCA‐Thai) were not statistically significant (p = 0.633), indicating no differences between the MoCA scores of both versions. When comparing total MoCA scores between participant groups, both CN and MCI had acceptable correlations (CCC >0.2) with a mean difference of 0.355 (‐4.720, 5.429) and ‐1.643 (9.001, 5.715), respectively, whilst AD had excellent correlation (CC >0.8) with a mean difference of 0.111 (‐6.496, 6.717). Subdomain scores between participant groups were not statistically significantly different except for Delayed Recall for all participants combined (p<0.05). In conclusion, there is adequate concurrent validity between the MoCA‐Thai and eMoCA‐Thai, making it a useful tool to help improve workflow and increase accessibility.
Amyloid‐Beta PET Synthesis from Structural MRI: A Potential Alternative Method for Alzheimer’s Disease Screening
Authors: Vega Fernando , Addeh Abdoljalil , MacDonald M. Ethan
Published: December 2023

Background

Amyloid‐beta and structural brain atrophy are known to be hallmarks of Alzheimer’s Disease (AD), and can be quantified with Positron Emission Tomography (PET) and structural Magnetic Resonance (MRI), respectively. PET scans use radiotracers that binds to amyloid‐beta molecules, whereas MRI measures changes in structural morphology. PET scans are difficult to perform due to cost (∼$5000/scan), invasiveness, and ionizing radiation exposure, making them inaccessible for screening early‐onset AD. Conversely, MRI is a cheaper (∼$500/scan), non‐invasive, and free from ionizing radiation technique, however, it cannot provide molecular information obtained from PET. There is a known relationship between amyloid‐beta and brain atrophy, hence, amyloid‐beta PET images might be synthesized from structural MRI using image translation, which is an advanced form of machine learning.

Method

An image translation algorithm was developed using the Open Access Series of Imaging Studies (OASIS‐3) dataset that provides 929 subjects with pairs of T1‐weighted MRI and amyloid‐beta PET images, where 609 are cognitively normal (CN) and 489 at different stages of cognitive decline based on Clinical Dementia Rating scores. The image translation algorithm implemented with Conditional Generative Adversarial Networks, shown in Figure 1, was trained with 550 pairs with 156 axial slices each of amyloid‐beta and MRI images. Eight models where generated with different parameters to assess their impact in the generalization quality, then compared in a sample of 334 subjects using Structural Similarity Index (SSIM) and Peak Signal‐to‐Noise Ratio (PSNR).

Result

Figure 2, compares the models performance based on SSIM and PSNR, where the best performing model generates synthetic PET images with a high degree of similarity with the real ones in Figure 3.

Conclusion

An image translation pipeline was implemented and explored by changing parameters that can affect the model performance, the developed models are robust against the different parameters that were changed and it demonstrates that amyloid‐beta PET images can be synthesized from structural MRI, reducing cost, invasiveness and increasing availability. Such a method could enable non‐invasive screening of early onset AD.
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

Background

Suicide 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).

Method

Twelve 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.

Result

In 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.

Conclusion

THC 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

Background

Tau 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.

Method

Resting 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.

Result

EM 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).

Conclusion

Greater 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

Background

Postmortem 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).

Method

Participants 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.

Conclusion

CA3 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

Background

Chronic 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.

Method

We 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.

Result

Ten 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.

Conclusion

The 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

Background

Our 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.

Method

Phase 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.

Result

Highly 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.

Conclusion

Network 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

Background

While 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.

Method

Ninety‐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.

Result

Subtle 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.

Conclusion

We 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

Background

While 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.

Method

We 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.

Result

7 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.

Conclusion

Our 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

Background

Chronic 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).

Method

sRHI (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).

Result

For 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.

Conclusion

Contact 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

:

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

Background

Delirium 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.

Methods

We 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.

Results

We 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).

Conclusion

Frailty 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
Cluster analysis of the longitudinal progression of plasma biomarkers and amyloid imaging in the Wisconsin Registry for Alzheimer’s Prevention
Authors: Wells Michael , Bilgel Murat , Jonaitis Erin M. , Langhough Rebecca E , Du Lianlian , Betthauser Tobey J , Blennow Kaj , Ashton Nicholas J. , Zetterberg Henrik , Johnson Sterling C , Jedynak Bruno Michel
Published: December 2023

Background

The analysis of the longitudinal progression of plasma biomarkers and amyloid imaging might lead to new insights in the early pattern of biomarker changes.

Method

Plasma Aβ42/Aβ40, pTau231/Aβ42, pTau181/Aβ42, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) were measured for n = 223 subjects and 1673 total visits in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) using Quanterix Simoa assays at the University of Gothenburg. Global distribution volume ratio (DVR) was computed from 11C‐Pittsburgh compound B PET scans. Inclusion criteria included Amyloid or CSF Amyloid positive status, and at least one plasma serial value. Trajectories spanning age 46.9 to 80.3 years old for the DVR and plasma biomarkers were estimated by fitting a vector field to the longitudinal data (https://arxiv.org/abs/2206.15215). A Louvain community clustering analysis was performed. The time from Amyloid positivity (DVR = 1.19; centiloid of 22) was also computed for all individual trajectories that crossed this threshold.

Result

The Louvain community clustering algorithm resulted in three distinct communities (Fig 1): no increase in DVR or plasma biomarkers (Green, n = 88(39.5%)); increase in DVR and all plasma biomarkers except NFL (Red, 41(18.4%)); and mixed DVR plus GFAP and NFL increase (Blue, 94(42.2%)). Time since Amyloid positivity (TSAP) was computed for the subset of subjects (n = 84) expected to cross the Amyloid positivity threshold. The Louvain communities as a function of TSAP are shown in Fig 2.

Conclusion

We identified three communities regarding the longitudinal progression of amyloid PET and plasma biomarker levels. Plasma biomarkers were dynamic up to 30 years before Amyloid positivity.
ApoE4 is associated with higher lipid peroxidation but not protein nitration in AD brains
Authors: Thorwald Max A , Godoy‐Lugo Jose A , Forman Henry Jay , Finch Caleb E
Published: December 2023

Background

Oxidative damage to proteins is associated with increased lipid peroxidation product hydroxynonenal (HNE) and nitrotyrosine (NT) during Alzheimer’s disease (AD). Because ApoE4 confers higher risk for AD, we assayed HNE and NT in AD and controls by ApoE allele. Oxidative damage was assayed in whole cell lysate and in lipid rafts (LR), where APP is enzymatically processed. Prefrontal cortex (Brodmann 8‐10) was compared with cerebellum, which has minimal AD pathology.

Method

Postmortem samples were age‐and sex matched for Braak scores of NFT. Homogenates from full thickness prefrontal cortex (n = 52) or cerebellum (n = 58) in isotonic buffer and mild detergent (RIPA; 1% NP40) were centrifuged (10,000g/1h; for the supernate fraction’). The same brain samples were processed for the subcellular LR fraction (Invent Biotechnologies; LR‐039); LR isolations were validated by ultracentrifugal fractionation. Samples were assayed by dot blots with antibodies for HNE or NT (Millipore, Burlington, MA).

Result

In prefrontal cortex supernates, AD increased HNE (+60%) and NT (+40%) above cognitively normal, while in cerebellum, only HNE increased. For LR, HNE increased in both prefrontal cortex (+165%) and cerebellum (+45%), while NT increased in AD prefrontal cortex (+40%), but not cerebellum. ApoE alleles differed in oxidative damage by brain region: E4 carriers had higher HNE (+35%) only in prefrontal cortex, while LR HNE was higher in E4 carriers of both regions (prefrontal cortex, +80%; cerebellum, +35%). NT did not differ in prefrontal cortex supernatant or LR by ApoE allele.

Conclusion

These findings extended prior findings on oxidative damage for HNE with AD by showing differences by brain region and by ApoE allele. HNE is formed from iron redox mediated lipid peroxidation, while protein nitration may be stimulated by aggregated amyloid independent of iron. AD was consistently associated with higher HNE and NT. The ApoE4 allele was more robustly associated with higher HNE in prefrontal cortex than cerebellum, while NT had no associations with E4, suggesting lipid peroxidation may be the predominant form of oxidative damage in the AD brain. The LR may be a hotspot for lipid peroxidation, with implications for APP processing which will be examined in future studies.
Imaging and quantifying microglial activation in vivo and ex vivo using diffusion MRI – with validation by immunohistochemistry
Authors: Sun Zhexian , Wu Wenjie , Xu Haonan , Flores Shaney , Hobbs Diana A. , Perrin Richard J. , Franklin Erin E. , Schindler Suzanne E. , Benzinger Tammie L.S. , Morris John C , Wang Yong , Wang Qing
Published: December 2023

Background

Alzheimer disease (AD) is the most common type of dementia.There is growing evidence that the amyloid plaques in postmortem AD human brains are surrounded by activated microglia. Using diffusion basis spectrum imaging (DBSI), we have previously observed increased cellular diffusivity in AD patients, suggesting increased microglia activation as a key pathology in AD. To better understand the underlying mechanism and further establish the noninvasive and nonradioactive DBSI biomarkers of microglia activation, we conducted a realistic Monte Carlo (MC) simulation to model diffusion MRI signals associated with microglia in various activation states.

Method

First, realistic microglia diffusion signals were generated using MC simulation with real 3D microglia geometry obtained from neuromorpho.org (Fig. 1A). We simulated different pathophysiological scenarios to validate DBSI’s capability in quantitatively detecting microglia activation (Fig. 1B). Second, we conducted and ex vivo MRI scans on human postmortem AD brain samples, followed by immunohistochemical (IHC) staining of microglia (Iba‐1) in aligned sections from the same tissue. DBSI cell apparent diffusion coefficients (ADC), reflecting microglia activation, were estimated and compared to quantitative histological assessments of microglia activation. Finally, in vivo DBSI was conducted on 200 participants who were classified into healthy control, preclinical AD, and early symptomatic AD groups based on cognitive assessments and measures of CSF amyloid (Aβ42) and pTau181.

Result

Two exemplary regions in grey matter (GM) and white matter (WM) of a postmortem AD brain were selected (Fig. 1C). We found that GM had significantly higher DBSI‐derived cell ADC than WM (Fig. 1D). Iba‐1 IHC revealed that WM had significantly larger average microglial area (p<0.005) and bigger max microglia larea (Fig. 1E‐F). MC Simulation was conducted on 700 microglia models. Microglial activation would result in an increased DBSI cell ADC (Fig. 1G). According to MC simulation, increased DBSI‐derived cell ADC in preclinical and early symptomatic AD indicated microglial activation in preclinical and early symptomatic AD (Fig. 1H).

Conclusion

DBSI‐derived cell ADC increases with microglial activation as assessed by quantitative Iba‐1 IHC. This finding is supported by MC simulation using real 3D microglia geometry. The study indicates that DBSI has the potential to provide non‐invasive MRI biomarkers of microglia activation.
Remote assessment of cognition with the unsupervised version of the Cogstate Brief Battery: Association of composite endpoints with Alzheimer’s disease biomarkers
Authors: Maruff Paul , Bransby Lisa , Yassi Nawaf , Buckley Rachel F. , Lim Yen Ying
Published: December 2023

Background

In people at risk of Alzheimer’s disease (AD), access to cognitive assessment can be increased through internet‐based registries, which can be linked to disease management clinics for comprehensive follow‐up. The Cogstate Brief Battery (CBB) has been optimized for unsupervised use in registries. This study aimed to determine relationships between performance on the unsupervised CBB, defined using conventional Cognigram and novel composite scores, and in‐clinic CSF AD biomarkers and cognition in middle‐aged adults at‐risk of AD.

Method

Seventy‐six cognitively unimpaired (CU) adults (67% female; Mage (SD) 58.4(6.7)) enrolled in the Healthy Brain Project (healthybrainproject.org.au) completed unsupervised CBB assessments, and subsequent in‐clinic assessment of AD biomarkers and cognition. CBB tests included DET (psychomotor‐function), IDN (attention), OCL (learning) and OBK (working memory). The Cognigram Learning/Working Memory Composite, and the Cognigram Psychomotor/Attention composite were derived from these. Two novel composites were also computed: the OCL speed/accuracy composite, and OCL‐OBK speed/accuracy composite. In‐clinic assessments included the International Shopping List, Logical Memory, and Digit Symbol Substitution Tests, and Mini Mental Status Examination to provide a Preclinical Alzheimer’s Cognitive Composite (PACC) score. CSF Aβ42, total tau (t‐tau), and tau phosphorylated at threonine 181 (p‐tau181) were measured by immunoassay (Roche Elecsys®) and CSF neurofilament light (NfL) was measured using ELISA. Associations with CSF Aβ42, t‐tau, p‐tau181, NfL and PACC were determined for each CBB composite with age, sex, education, APOE4 and time difference between unsupervised and in‐clinic assessment controlled statistically.

Result

The Cognigram Learning/Working memory composite, the OCL speed/accuracy composite, and the OCL‐OBK speed/accuracy composite were associated with PACC scores and with t‐tau, p‐tau181, and NfL levels. Magnitude of relationships were similar across composites (Table 1). No cognitive composite was associated with CSF Aβ42. Performance on the Cognigram Psychomotor/Attention composite was unrelated to AD biomarkers or PACC scores.

Conclusion

In CU adults, unsupervised performance on CBB composites containing learning and working memory measures were associated strongly with in‐clinic neuropsychological outcomes and AD biomarkers. Remote measurement of cognition can validly assess aspects of learning and working memory disrupted by early AD processes such as increases in tau, and could be useful for identification of individuals with early disease.
Functional connectivity trajectories in genetic frontotemporal dementia
Authors: Zhang Liwen , Flagan Taru M. , Staffaroni Adam M. , Häkkinen Suvi , Brown Jesse A. , Mandelli Maria Luisa , Rosen Howard J. , Kantarci Kejal , Ramos Eliana Marisa , Tempini Maria Luisa Gorno , Miller Bruce L , Seeley William W. , Lee Suzee E. ,   ARTFL/LEFFTDS/ALLFTD Consortia
Published: December 2023

Background

Characterizing disease trajectories in frontotemporal lobar degeneration (FTLD) is essential to determine the optimal timing for initiating therapeutic interventions, and there is an urgent need for novel and sensitive disease biomarkers. Intrinsic connectivity network (ICN) mapping using task‐free fMRI is a promising biomarker which reveals early abnormalities even before symptomatic onset (Dopper et al. 2014; Lee et al. 2016). Yet, ICN trajectories from the presymptomatic to symptomatic stages in FTLD mutation carriers remain unclear.

Method

In this cross‐sectional study, we used UCSF and ALLFTD Consortia data to study 129 carriers with variants in MAPT (presymptomatic/prodromal/symptomatic: 34/4/7), C9orf72 (30/9/12) and GRN (22/4/7). Using cross‐sectional data to construct ICN trajectories by genotype, we built separate generalized additive models for each genetic group to estimate non‐linear relationships between standardized connectivity changes and disease age across clinical stages. ICN connectivity was based on seed‐based analyses for networks associated with common clinical syndromes for each genetic group (i.e., salience and default mode [MAPT/C9orf72/GRN], corticobasal syndrome [MAPT/GRN], progressive supranuclear palsy syndrome [MAPT], sensorimotor and medial pulvinar‐related [C9orf72], and non‐fluent variant primary progressive aphasia (nfvPPA) syndrome networks [GRN]). We included 127 healthy controls as a reference to calculate ICN z‐scores for each carrier. Each carrier’s disease age was defined as the difference between the carrier’s chronological age and estimated age of onset based on multimodal measures of structural imaging, fluid biomarker and clinical assessments (Staffaroni et al. 2022).

Result

In MAPT+, presymptomatic carriers showed declining salience network connectivity starting approximately 30 years before estimated onset, which plateaued about 20 years before onset. In C9orf72+, salience network hyperconnectivity emerged about 30 years before onset and declined throughout the presymptomatic and symptomatic stages. For GRN+, connectivity changes as a function of disease age were found within the salience and nfvPPA networks, with connectivity stable until around 10 years before estimated onset, followed by decline starting in the late presymptomatic phase and continuing through the prodromal and symptomatic stages.

Conclusion

These findings demonstrate that FTLD genes show distinct ICN trajectories throughout the clinical spectrum. These results help pave the way for determining the optimal timing to initiate therapeutic interventions.
Chosen Family? Rethinking “Relationship Status” in LGB Cognitive Aging Research
Authors: Hanes Douglas William
Published: December 2023

Background

Existing studies have shown the importance of marital status and quality on later‐life cognitive health, including dementia risk and likelihood of timely dementia diagnosis. Yet, much evidence comes from different‐sex couples’ experiences, for whom marriage remains the norm and unmarried persons face social and material costs. In contrast, where same‐same marriage is legal in North America and Europe, marriage has not yet become the norm: same‐sex couples (SSCs) have lower marriage rates than different‐sex couples. SSCs also tend to structure their relationships differently across a range of domains, from household labor to sexual nonmonogamy. Throughout Europe and North America, older lesbian and gay people are also more likely to be single, to live alone, and to have no living children than straight or bisexual people; as a result, the former tend to rely less on partners or biological family to meet their social needs. Unlike straight men, for example, gay and bisexual men tend to rely less on their partners or daughters to forge and maintain social and community connections, instead relying on “chosen families”.

Method

Given their unique prominence for sexual minorities, this paper uses population‐based surveys from the US (HRS) and Europe (ELSA and SHARE) to investigate measures of non‐biologically familial social bonds, including whether measures of friendship, social connectedness, and community involvement function similarly to marital status.

Result

In the US, which has the highest marriage rates and a deeply entrenched “marriage culture”, LGB participants in the HRS (1998‐2018; n = 23,035) who indicate having never been married perform better cognitively at baseline than married LGB people (β = 1.5; p = 0.05), while never‐married straights perform worse (β = ‐0.9; p <0.01).

Conclusion

Relationship factors have a different association with cognitive health for LGB people than straight people, yet these remain unexplored in their effects on cognitive aging and queerer pathways to good cognitive health.