bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep duration in relation to dementia risk in the UK Million Women Study
Authors: Wong Angel TY , Reeves Gillian K , Beral Valerie , Floud Sarah
Published: December 2022

Background

Sleep is often disrupted in people with dementia. To help assess whether any association between sleep duration and dementia may be the consequence of pre‐clinical disease or causal we examined dementia risk in relation to follow‐up time after reporting sleep duration in a large UK prospective study of women.

Method

About 1.3 million women were recruited in median year 1998 (IQR 1997‐1999) in England and Scotland; in 2001 (IQR 2000‐2003), ∼830,000 reported their usual hours of sleep per 24 hours. They were followed for any mention of dementia in hospital records, the first mention of which was the main outcome. Cox proportional hazards regression was used to estimate dementia detection risk ratios (RRs and 95% confidence intervals [CI]) for <6, 6, 9, and >9 hours of sleep, compared to 7‐8 hours, respectively, during follow‐up periods of 0‐4, 5‐9, 10‐14 and 15+ years after sleep duration was reported. Adjustment was made for sociodemographic factors, lifestyle factors, and other characteristics.

Result

Women most commonly reported sleeping for 7‐8 hours (67%), with substantially fewer women reporting short sleep duration (<6 hours [5%], 6 hours [18%]) or long sleep duration (9 hours [7%], >9 hours [3%]). Over a mean 17 years of follow‐up (with <2% lost to follow‐up) ∼34,000 women had at least one hospital record of mentioning dementia. Compared to 7‐8 hours, there was no clear and consistent association between short sleep duration (<6, 6 hours) and dementia detection risk throughout the follow‐up periods. Long sleep duration (9, >9 hours) was associated with higher dementia detection risk in the first 5 years of follow‐up (e.g. RR for >9 vs 7‐8 hours sleep: 2.78 [95% CI, 2.22‐3.48]), but these RRs declined rapidly as follow‐up time increased and had largely disappeared 15+ years of follow‐up (1.18 [1.08‐1.28]), suggesting that the short‐term associations are the consequence of pre‐clinical disease. Associations by follow‐up period did not notably differ for Alzheimer’s disease, vascular dementia, and unspecified dementia.

Conclusion

Increased sleep duration appears to be a consequence of pre‐clinical dementia but there is little to suggest a long‐term causal association of sleep duration with dementia risk in women.
Nighttime behaviors, but not insomnia, correlates with cognition and biomarkers of dementia
Authors: Zawar Ifrah , Quigg Mark S , Mattos Meghan K , Manning Carol A
Published: December 2022

Background

While sleep disturbances appear to be risk factors in the progression of Alzheimer’s disease (AD) and other dementias, little is known about the prevalence across dementia severity and the potential influence on the trajectory of cognitive decline.

Method

We used the prospective National Alzheimer Coordinating Center Uniform Data Set to evaluate the hypotheses that the prevalence of insomnia differs by definition and by stage of cognitive impairment, that certain sleep features track with established biomarkers of AD, and that longitudinal changes in sleep disorders affect cognition and AD biomarkers. We conducted cross‐sectional analyses to determine the prevalence of clinician‐determined insomnia and nighttime behaviors (nighttime restlessness, agitation, daytime sleepiness) in normal, mild cognitive impairment (MCI), and demented individuals, as defined by Montreal Cognitive Assessment (MoCA) cut‐off scores obtained during the patient’s first visit. We evaluated mean MoCA scores, hippocampal volumes, and CSF phosphorylated tau:beta amyloid ratios obtained near the first visit using Analysis of Variance (ANOVA) with age as a covariate. In longitudinal evaluations, we classified changes in insomnia and nighttime behaviors as “none”, “remitted”, “acquired”, or “steady” between the first and last visits. Similar changes in MoCA scores and hippocampal volumes were assessed with repeated‐measure ANOVA.

Result

The prevalence of clinician‐identified insomnia at initial visits was 15%, 17%, and 13% for normal, MCI, and dementia groups respectively. Prevalence of clinician‐identified nighttime behaviors was 13%, 19%, and 27% respectively. Insomnia was significantly associated with higher MoCA scores, larger hippocampal volumes, and higher pTau:Beta values, indicating those with clinician‐identified insomnia had better cognition and less neurodegeneration than individuals who clinicians identified to be without insomnia. In contrast, the presence of nighttime behaviors were associated with significantly worse cognition, smaller hippocampal volumes, and lower pTau:Beta. Similar findings were seen between longitudinal associations of sleep disorders and cognition and hippocampal volumes.

Conclusion

Our findings suggest that the clinician determination of insomnia may be under‐recognized in patients with cognitive impairment seen in memory disorders clinics, and that nighttime behaviors especially when reported by family members may better reflect sleep disturbances, the biological underpinnings of AD, and have diagnostic specificity in AD over insomnia.
Substantia nigra integrity is associated with poorer recognition memory for novel stimuli in early Alzheimer’s disease
Authors: Krohn Friedrich , Sarkar Mousumi , Schütze Hartmut , Yakupov Renat , Spottke Annika , Hämmerer Dorothea , Schneider Anja , Heneka Michael T. , Fließbach Klaus , Kilimann Ingo , Teipel Stefan , Jessen Frank , Duzel Emrah , Betts Matthew
Published: December 2022

Background

The substantia nigra/ventral tegmental area (SN/VTA), the brain’s most prominent dopamine source, is involved in novelty exploration and episodic memory. Using a novelty detection task combined with neuromelanin‐sensitive MRI, this work aimed to investigate the relationship between SN integrity, neural novelty response and subsequent recognition memory performance in individuals with early Alzheimer’s disease.

Method

79 healthy subjects, 54 participants with subjective cognitive decline (SCD), 18 with mild cognitive impairment (MCI), and 10 individuals with ADD from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study performed a previously published scene novelty and encoding task (“FADE”) using 3T fMRI. Additional 3D T1‐weighted FLASH images were collected to visualize and quantify the volume and MRI contrast in the SN.

Linear regression models were generated to assess for associations between either SN volume and median MRI contrast, considered as proxy integrity measures, with functional activity during novelty and subsequent recognition memory performance (dprime). We used site, gender, age and years of education as covariates. We assessed AD pathology in a subsample of individuals with CSF biomarkers (n = 71).

Result

We observed a significant decline in SN volume (p = 0.003) but not MRI contrast in ADD compared to healthy controls. The SN volume in the whole sample correlated positively with recognition memory for novel stimuli (r = 0.35; p = 0.02,). This association held in the CSF subsample (r = 0.31; p = 0.034) and also after correcting for levels of both tau (phosphotau, r = 0.57; p = 0.0284,) and amyloid (Abeta 42/40 ratio, r = 0.46; p = 0.03,). Additionally, SN median MRI contrast significantly correlated with novelty responses in the hippocampus in the CSF subsample and also in amyloid positive but not negative (Abeta 42/40 ratio<0.08, n = 26) individuals. Finally, recognition memory (p<0.001) was significantly decreased in Abeta positive compared to negative individuals.

Conclusion

We show that significant degeneration to the SN in AD dementia and pathological Abeta 42/40 levels are associated with poorer recognition memory for novel stimuli. Moreover, associations between SN median MRI contrast and novelty responses differed between amyloid positive and negative individuals. These results indicate that degeneration to the SN may contribute to memory dysfunction in AD dementia which may be linked to pathological amyloid levels.
Plasma glial fibrillary acidic protein is associated with reactive astrogliosis assessed via 18F‐SMBT‐1 PET
Authors: Chatterjee Pratishtha , Dore Vincent , Pedrini Steve , Krishnadas Natasha , Thota Rohith N , Bourgeat Pierrick , Rainey‐Smith Stephanie , Burnham Samantha C , Fowler Christopher , Taddei Kevin , Mulligan Rachel S , Ames David , Masters Colin L. , Fripp Jurgen , Rowe Christopher , Martins Ralph N , Villemagne Victor L
Published: December 2022

Background

Reactive astrogliosis is an early event along the Alzheimer’s disease (AD) continuum. We have shown that plasma glial fibrillary acidic protein (GFAP), reflecting reactive astrogliosis, is elevated in cognitively unimpaired individuals with preclinical AD (Chatterjee et al., 2021). We reported similar findings using 18F‐SMBT‐1, a PET tracer for monoamine oxidase B (MAO‐B) (Villemagne et al., 2022). To provide further evidence of their relationship with reactive astrogliosis we investigated the association between GFAP and 18F‐SMBT‐1 in the same participants.

Method

Plasma GFAP, Aβ42 and Aβ40 levels were measured using the Single Molecule Array platform in 71 participants comprising 54 healthy controls (12 Aβ+ and 42 Aβ‐), 11 MCI(3 Aβ+ and 8 Aβ‐) and 6 probable AD(5 Aβ+ and 1 Aβ‐) patients from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing cohort. These participants also underwent 18F‐SMBT‐1 and Aβ PET imaging. Aβ imaging results were expressed in Centiloids (CL; ≥20 CL classified as Aβ+). 18F‐SMBT‐1 Standard Uptake Value Ratio (SUVR) were generated using the subcortical white matter as reference region. Linear regression analyses were carried out using plasma GFAP levels as the dependent variable and regional 18F‐SMBT‐1 SUVR as the independent variable, before and after adjusting for age, sex, soluble Aβ (plasma Aβ1‐42/Aβ1‐40 ratio) and insoluble Aβ (Aβ PET).

Result

Plasma GFAP was significantly associated with 18F‐SMBT‐1 SUVR in brain regions of early Aβ deposition, such as the supramarginal gyrus (SG, β=.361, p=.002), posterior cingulate (PC, β=.308, p=.009), lateral temporal (LT, β=.299, p=.011), lateral occipital (LO, β=.313, p=.008) before adjusting for any covariates. After adjusting for covariates age, sex and soluble Aβ, GFAP was significantly associated with 18F‐SMBT‐1 PET signal in the SG (β=.333, p<.001), PC (β=.278, p=.005), LT (β=.256, p=.009), LO (β=.296, p=.004) and superior parietal (SP, β=.243, p=.016). On adjusting for age, sex and insoluble Aβ, GFAP was significantly associated with SMBT‐1 PET in the SG (β=.211, p=.037) however only a trend towards significance was observed in the PC (β=.186, p=.052) and LT (β=.171, p=.067) (Figure 1).

Conclusion

There is an association between plasma GFAP and regional SMBT‐1 PET that is primarily driven by brain Aβ load.
Increased incidence of dementia following herpesvirus infection in the Korean population
Authors: Shim YongSoo
Published: December 2022

Background

Herpesviruses affect the development of dementia. We investigated the association between herpes infection and subsequent diagnoses of dementia.

Method

Data from the National Health Insurance Service of South Korea were used. Patients aged ≥ 50 years with the relevant diagnostic codes in the reference year 2009 were included and prospectively reviewed from January 2010 to December 2018. All study participants were followed from the index date until the onset of dementia, death, or the study endpoint.

Result

The three cohorts comprised 92,095 patients with herpes simplex virus (HSV) infections, 97,323 patients with varicella‐zoster virus (VZV) infections, and 183,779 controls. During the follow‐up period, 15,831 (17.19%) subjects with HSV infection and 17,082 (17.55%) VZV‐infected subjects, compared to 27,028 (14.17%) control subjects, were subsequently diagnosed with dementia (all, P<0.001). The adjusted hazard ratio for developing dementia was found to be 1.18 (95% confidence interval [CI]; 1.16‐1.20) in HSV and 1.09 (95% CI; 1.07‐1.11) in VZV patients (all, P<0.001). HSV1 infections such as oral or ocular subtypes, but not HSV2, anogenital subtype, were associated with dementia, including several subtypes such as Alzheimer’s disease (AD), vascular dementia, and dementia with Lewy bodies. VZV infection is also associated with AD.

Conclusion

In this Korean nationwide population‐based cohort study, both HSV and VZV infections were associated with a higher risk of dementia, particularly AD. Among the subtypes of HSV infection, HSV1 is associated with a risk of dementia. Further studies including appropriate public health interventions could evaluate the causality of these relationships.
Positive Aspects of Caregiving Moderates the Relationship between Family Functioning and Caregiver Burden in Dementia
Authors: Zammitti Melissa G , Chapman Kimberly R , Tremont Geoffrey
Published: December 2022

Background

Worse family functioning may predict greater caregiver burden for families dealing with dementia. However, experiencing positive aspects of dementia caregiving could mitigate this relationship. The current work explored whether the relationship between family functioning and caregiver burden depends on positive aspects of caregiving. We hypothesized that greater endorsement of positive aspects of caregiving would attenuate the relationship between family functioning and caregiver burden.

Method

Cross‐sectional baseline data from dementia caregivers enrolled in a caregiver intervention study were analyzed (n = 163). Dementia caregivers self‐reported demographic data. Family functioning, caregiver burden, and positive aspects of dementia caregiving were captured, respectively, using a brief version of the Family Assessment Device (FAD; Epstein et al., 1983), the Zarit Burden Interview (ZBI; Zarit et al., 1986), and the Positive Aspects of Caregiving scale (PAC; Tarlow et al., 2004). Linear regression was used to determine if PAC moderated the relationship between FAD and ZBI controlling for caregiver relationship.

Result

The overall model (R2 = 0.28, F(4, 158) = 15.6, p<.001) and interaction term (b = ‐0.06, 95%CI [‐0.10, ‐0.03] were significant. At low and average levels of PAC there was a significant negative relationship between FAD and ZBI such that worse family functioning predicted greater caregiver burden. At high levels of PAC there was no relationship between FAD and ZBI.

Conclusion

Consistent with expectation, the relationship between family functioning and caregiver burden depended on positive aspects of caregiving. Dementia caregivers who do not strongly identify with the positive aspects of their caregiver role may be particularly susceptible to experiencing increased burden in the face of low family support. Both the individual and the family of the caregiver may benefit from intervention strategies that assist in recognizing and cultivating the positive aspects of dementia caregiving.
Scaffold morphing and in silico studies of potential BACE1 (β‐secretase) inhibitors: A hope for newer dawn in anti‐Alzheimer therapeutics
Authors: Singh Manjinder , Bhatia Shiveena , Sharma Pratibha , Kaur Maninder , Singh Thakur Gurjeet
Published: December 2022

Background

AD (Alzheimer’s disease) is the prime causes for 65‐85% cases of senile dementia occurs due to the plaques aggregation and tangles formation in various parts of brains neurons (cortical and hippocampal) leading to brain cell death. The major cause of AD is the extracellular plaques accretion made of β‐amyloid protein. The β‐secretase enzyme also known as BACE‐1 is the key player behind this phenomenon catalyzing the rate determining step of the reactions generating β‐amyloid. Therefore, efforts are being applied for research and development of novel entities that can inhibit the BACE‐1 enzyme and thus halting the plaque build‐up.

Method

In our study, we analyzed some of the analogues of Elenbecestat, which is a β‐secretase inhibitor currently in clinical trials designed by using scaffold morphing and structure‐based designing approach with a superior therapeutic profile, followed by in silico screening i.e. pharmacokinetics and docking methodologies.

Result

The designed molecules showed good interactions with the active pockets (Asp32 and Asp228, catalytic dyad residues) of β‐secretase protein and having drug likeliness properties.

Conclusion

Henceforward, molecular dynamic studies are required to fully establish their possible utility as the promising BACE1 inhibitors.
Plasma biomarkers for Alzheimer's disease: from amyloid to CNS derived extracellular vesicles, overview of changes through age, sex and risk factor in control and AD populations
Authors: Boyer Emilien , Kienlen‐Campard Pascal , Hanseeuw Bernard J
Published: December 2022

Background

Hallmark proteins pathogenic in Alzheimer's disease (AD), amyloid and tau, can now be quantified in plasma samples using single‐molecule array (SIMOA). However, proteins are not only circulating in plasma, but are also present in nervous system‐derived extracellular vesicles (NDBEs) secreted by neurons in the plasma. We aim to quantify plasmatic NBDEs to evaluate whether their number or content are modified in symptomatic AD.

Method

Plasma samples were obtained in clinically normal (CN) participants (N = 76, sex ratio F/M = 1.5, mean age 57.5 ± 16.3, Apoε4 positive n=31, Apoε4 negative n=43) and in patients with symptomatic AD (N=17, sex ratio F/M = 0.7, mean age 70.1 ± 7.6). Quantification of amyloid 42 – 40 peptides and Tau protein was achieved with SIMOA multiplex analysis. For relative quantification of NDBEs circulating in plasma, we used DELFIA ELISA immunoassay with anti‐neuronal cell adhesion molecule (NCAM1) antibody. Normalization to the total number of vesicles was done using an antibody targeting CD81, a ubiquitous vesicle marker.

Result

We observed a significant decrease of Aβ42 in AD patients (p < 0.05), and in CN carrying an Apoε4 allele (p < 0.05). The ratio Aβ42/40 was lower in AD patients (p < 0.05) and the ratio Tau/Aβ42 was higher (p < 0.05). In CN, the relative amount of NDBEs in plasma was correlated with circulating Aβ42 (p < 0.0001, R² 0.2699) and Tau (p < 0.0001, R² 0.2753) such that greater numbers of NBDEs were associated with lower concentrations of proteins in circulating plasma. Amount of NDBEs do not seem to change with age, Apoε4 status or in AD patients.

Conclusion

Levels of Ab42, ratios Aβ42/40 and Tau/Aβ42 in plasma are significantly different in patients with symptomatic AD, and between ApoE4 carriers and non‐carriers among CN individuals. However, the number of NBDEs is negatively associated with the concentrations of these proteins, suggesting that these proteins are encapsulated in NBDEs. Future work will analyze the content of the vesicles to confirm that hypothesis.
APOE4 exacerbates α‐synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy Body pathology
Authors: Jin Yunjung
Published: December 2022

Background

Accumulating evidence demonstrates that 40‐50% of Alzheimer’s disease (AD) brains present with concomitant Lewy pathologies at autopsy, suggesting that α‐synuclein (α‐SYN) aggregation is likely involved in the pathogenesis of AD. Interestingly, the genome‐wide association study (GWAS) revealed that the ε4 allele of APOE (APOE4) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying the important role of APOE4 in both amyloid β (Aβ) and α‐SYN pathogenesis. However, how APOE4 modulates the α‐SYN aggregation in AD is still unclear.

Method

We performed biochemical analyses measuring α‐SYN levels on a pathologically confirmed human AD cohort (N = 469) obtained from the Mayo Clinic Brain Bank, wherein 54.4% of our cohort presented with co‐morbid α‐SYN pathology upon diagnosis of AD with Lewy Body pathology (hereinafter referred to as AD+LB), which was subdivided into APOE4 non‐carriers (APOE4−) and carriers (APOE4+). To determine the seeding activity of α‐SYN, we performed Real‐time quaking‐induced conversion (RT‐QuIC) assays with the soluble TBS protein fractions of the brain lysates. The cytotoxicities of the amplified α‐SYN seeds were tested with MTT assay for cell viability and neuronal outgrowth measurement by immunofluorescence staining with human induced pluripotent stem cells (iPSC)‐derived neurons.

Result

We found that AD+LB cases showed the significantly higher seeding activity of α‐SYN compared to AD cases without LB pathologies. Furthermore, APOE4+
AD+LB brains had the highest α‐SYN seeding activity compared to AD+LB APOE4−
cases. The α‐SYN seeding activity was associated with the level of α‐SYN, tau, or APOE aggregates, but not Aβ. Finally, we showed that the amplified α‐SYN aggregates derived from AD+LB APOE4+
had highest protease resistance and cytotoxicities in iPSC‐derived neurons.

Conclusion

These findings suggest that APOE4 modulates the conformation of α‐SYN seeds which leads to high seeding activity and toxicity of α‐SYN in AD.
Development and Evaluation of a Natural Language Processing Annotation Tool (NAT) to Facilitate Phenotyping of Cognitive Status in Electronic Health Records
Authors: Magdamo Colin G. , Noori Ayush , Liu Xiao , Tyagi Tanish , Li Zhaozhi , Kondepudi Akhil , Alabsi Haitham , Rudmann Emily , Wilcox Douglas , Brenner Laura , Robbins Gregory K. , Moura Lidia Maria V. , Hsu John , Zafar Sahar F. , Benson Nicole , Serrano‐Pozo Alberto , Dickson John , Hyman Bradley T. , Blacker Deborah , Westover M Brandon , Mukerji Shibani , Das Sudeshna
Published: December 2022

Background

Electronic Health Records (EHR) with large sample sizes and rich information offer great potential for dementia research, but current methods of phenotyping cognitive status are either not scalable or suffer from inaccuracies. Our objective is to evaluate whether deep learning Natural Language Processing (NLP)‐powered semi‐automated annotation can improve the speed and reliability of chart reviews for phenotyping cognitive status.

Method

In this study we developed and evaluated a semi‐automated NLP‐powered annotation tool (NAT) to facilitate phenotyping of cognitive status. Clinical experts adjudicated the cognitive status of 627 patients at Mass General Brigham (MGB) Healthcare using NAT or traditional chart reviews. Patient charts contained EHR data from two datasets: (1) Records from January 1, 2017 to December 31, 2018 for 100 Medicare beneficiaries from the MGB Accountable Care Organization (ACO), and (2) Records from 2‐years pre‐COVID diagnosis to the date of COVID diagnosis for 527 MGB patients. All EHR data from the relevant period were extracted; diagnosis codes, medications, and laboratory test values were processed and summarized. Clinical notes were processed through a deep learning NLP algorithm and a web tool was developed to present an integrated view of all data. Cognitive status was rated as cognitively normal, cognitively impaired, or undetermined. Assessment time and interrater agreement of NAT compared to manual chart reviews for cognitive status phenotyping was evaluated.

Result

NAT adjudication provided higher interrater agreement (Cohen k = 0.89 vs. k = 0.80) and significant speed up (time difference mean [SD]: 1.4 [1.3] minutes, P < 0.001; ratio median [min, max]: 2.2 [0.4, 20]) over manual chart reviews. There was moderate agreement with manual chart reviews (Cohen k = 0.67). In the cases that exhibited disagreement with manual chart review, NAT adjudication was able to produce assessments that had broader clinical consensus due to its integrated view of highlighted relevant information and semi‐automated NLP features.

Conclusion

NAT adjudication improves the speed and reliability for phenotyping cognitive status compared to manual chart reviews. This study underscores the potential of an NLP‐based clinically adjudicated method to build large‐scale dementia research cohorts from EHR.
The effect of altered nitric oxide bioavailability on the interaction of obesity and Alzheimer’s disease. Exploration of whether a high fat diet produces early cognitive decline in an Alzheimer’s mouse model.
Authors: White Ginger L
Published: December 2022

Background

Alzheimer’s disease (AD) can be predicted by obesity and vascular risk factors. Obesity and AD are associated with vascular dysfunction, resulting in reduced peripheral and cerebral blood flow. Obesity is associated with reduced nitric oxide (NO) bioavailability, which contributes to reduced blood flow, the accumulation of β‐amyloid (Aβ), and eventual cognitive decline in AD. In animal models of AD, obesity or high fat diet exacerbates cognitive decline. The APPswe/PS1dE9 (APP/PS1) mouse, a model of beta amyloid neuropathology, demonstrates significant NO substrate dysfunction. NO substrate dysfunction and obesity potentially initiates metabolic and vascular dysfunction that can accelerate cognitive function decline. We investigated the impact of a high‐fat diet (HFD) on cognitive performance (discrimination reversal) in transgenic (Tg) and non‐transgenic (Non‐Tg) APP/PS1 mice prior to evaluating the role of NO in AD and obesity.

Method

Female APP/PS1 mice were split into four groups: Non‐Tg Chow (n = 9), Non‐Tg HFD (n = 5), Tg Chow (n = 9), and Tg HFD (n = 14). Mouse operant chambers with two nose poke ports and a dipper for delivering sucrose solution (15%) were used. Discrimination reversal procedure involved nose pokes in the left or right nose poke port produced access to 15% sucrose under a fixed ratio (FR) 1 schedule of reinforcement. Once the performance met criteria, the “correct” nose poke port was switched.

Result

Tg mice averaged fewer sessions to meet criteria in training. Non‐Tg and Tg mice on HFD failed to learn the discrimination to criteria and never experienced reversals. Non‐Tg mice on chow learned the discrimination multiple times. Only one Tg mice fed chow learned. Mice fed the chow diet received more sucrose reinforcers compared to mice fed the HFD.

Conclusion

Although HFD‐fed mice responded at lower rates, on average, they still made substantial numbers of responses suggesting that the failure to obtain the discrimination was not simply a result of a motivational deficit. Non‐Tg chow‐fed subjects made fewer errors than Tg chow‐fed subjects. Tg HFD‐fed mice originally made as many errors as their chow‐fed littermates but made more errors over the course of the study. Future research will investigate the impacts of decreased NO bioavailability.
Understanding characteristics of persons with early onset dementia in the UCLA Alzheimer’s and Dementia Care Program
Authors: Lee David R , Romero Tahmineh , Serrano Katherine , Panlilio Michelle , Rojas‐Parra Abel , Matsuno Lauren , Mendez Mario F. , Reuben David
Published: December 2022

Background

Although early onset dementia (EOD) accounts for approximately 5% of persons living with dementia (PLWD), there is limited understanding of their demographic characteristics, behavioral symptoms, and caregiver measures, especially in comparison to persons with older onset dementia (OOD).

Method

The UCLA Alzheimer’s and Dementia Care Program is a comprehensive dementia care management program that has served over 3450 PLWD since 2012. This retrospective study compares baseline visit characteristics of participants with EOD (≤ 65 years of age) to participants with OOD (≥ 80 years of age). Variables include patient and caregiver demographics, Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores, Mini Mental State Exam (MMSE), Modified Caregiver Strain Index (MCSI), caregiver PHQ‐9, and insurance status. Fisher exact tests were used to test differences between age groups.

Result

The attached table presents comparisons of the 177 participants with EOD and 731 with OOD. Compared to OOD, persons with EOD were more likely to be men, college graduates, dually insured, have unpaid caregivers, live alone, and be married. Caregivers for persons with EOD were most often spouses, whereas caregivers for persons with OOD were more often children. Although participants had similar MMSE scores, NPI‐Q severity and NPI‐Q distress scores were higher among persons with OOD compared to EOD.

Conclusion

There are important differences in demographic characteristics, caregiving status, and behavioral symptoms among persons with EOD compared to those with OOD. Understanding the unique challenges, needs, and resources of persons with EOD may provide valuable insight to adapt dementia care to better meet their needs.
Analytical performance of the Lumipulse® G β‐Amyloid 1‐40 Plasma and Lumipulse® G β‐Amyloid 1‐42 Plasma RUO assays
Authors: Vandijck Manu , Degrieck Rosina , Denoyette Mario , Delanote Jarne , De Jonge Maarten , De Decker Bart , Bastard Nathalie Le , Vandenbroucke Ina
Published: December 2022

Background

Current research indicates that plasma β‐amyloid1‐42/β‐amyloid1‐40 ratio has the potential for application in clinical settings and clinical trials to predict brain β‐amyloid burden. It could reduce the number of lumbar punctures (for CSF biomarker testing) or Aβ‐PET scans in light of clinical trial recruitment and could serve as a tool to evaluate target engagement and efficacy of disease‐modifying drugs. The aim of the current study was to demonstrate the analytical performance of the newly developed Lumipulse G β‐Amyloid 1‐40 Plasma and Lumipulse G β‐Amyloid 1‐42 Plasma RUO assays.

Method

The LUMIPULSE G system is a chemiluminescent enzyme immunoassay platform enabling fully automated processing of samples using ready‐to‐use immunoreaction cartridges. Time to result in these single use test cartridges takes about 30 minutes. The analytical performance of the newly developed Lumipulse G β‐Amyloid 1‐40 Plasma and Lumipulse G β‐Amyloid 1‐42 Plasma RUO assays (using respectively 2G3 and 21F12 antibody for capturing and 3D6 antibody ALP‐conjugate for detection; two‐step immunoassay method) was determined. Parameters analysed were precision, sensitivity, linearity, and potential impact of interfering substances. The studies included a series of buffer‐ and K2EDTA plasma‐based samples at different concentration levels, each tested in several replicates (70 µL/replicate (Aβ1‐40); 110 µL/replicate (Aβ1‐42)) sized to the different parameters tested.

Result

The total within‐lab variability of both assays was ≤6 % CV confirming high precision of the LUMIPULSE G system. Using low β‐amyloid concentrated plasma samples, the observed LoD was 0.44 pg/mL (Aβ1‐40) and 0.37 pg/mL (Aβ1‐42), and the LoQ was 0.44 pg/mL (Aβ1‐40) and 0.43 pg/mL (Aβ1‐42). Linearity was shown across the assay range (0 – 5000 pg/mL (Aβ1‐40); 0 – 1000 pg/mL (Aβ1‐42)). No significant impact of commonly tested endogenous substances (bilirubin, chyle, triglycerides, rheumatoid factor (RF) and human anti‐mouse antibodies (HAMA)) was observed, except for haemoglobin.

Conclusion

The analytical performance studies demonstrate – amongst other characteristics – low variability and high sensitivity enabling measurement of Aβ1‐40 and Aβ1‐42 in plasma. The Lumipulse G β‐Amyloid 1‐40 Plasma and Lumipulse G β‐Amyloid 1‐42 Plasma RUO assays are now ready to be explored further for clinical utility in various contexts of use.
Long‐read sequencing and complete telomere to telomere human reference genome provide deeper insight into human brain transcriptomics
Authors: Heberle Bernardo Aguzzoli , Brandon Jason A , Nations Kayla , Page Madeline L , Wadsworth Mark E , Dickson Dennis W. , Miller Justin B , Fryer John D. , Ebbert Mark T.W.
Published: December 2022

Background

RNA‐seq experiments have traditionally been done with short‐read sequencing technologies that, by nature, collapse all RNA isoforms for a given gene into a single expression measurement—a major oversimplification of the underlying biology. Collapsing all RNA isoforms for a single gene severely limits our ability to characterize all RNA isoforms and determine their individual downstream functions. While computational approaches for assembling short reads into full transcripts exist, these methods are inherently structurally inaccurate, especially when compared to full‐length sequencing possible with long‐read sequencing technologies. In contrast, long‐read sequencing technologies can sequence entire RNA molecules, allowing researchers to accurately quantify expression for the complete set of RNA isoform species, including de novo RNA isoforms. Long‐read sequencing is especially well suited for discovering novel isoforms in the recently released telomere‐to‐telomere (T2T) human reference genome (CHM13). The new CHM13 genome assembly resolved highly homologous regions that are challenging to study with short‐reads. Here we sequenced post‐mortem human brain tissue with long‐reads and aligned them to CHM13 to explore novel gene bodies and transcript isoforms.

Methods

We sequenced pre‐frontal cortex tissue from four post‐mortem human brain samples using Oxford Nanopore Technologies long‐read sequencing for PCR amplified cDNA. Data were basecalled using Guppy, reads were aligned to the CHM13 human reference genome using minimap2, and transcripts were assembled and quantified with the Bambu package in R.

Results

Among other findings, we discovered 84 new, high‐confidence gene bodies expressed in all four samples with at least 5 reads in each sample. We also found 223 novel RNA isoforms in previously annotated gene bodies. Of these 223 novel isoforms, 29 aligned to medically relevant genes such as MAOB, HLA‐DRB1, and ABO.

Conclusions

Our results suggest long‐reads aligned to the CHM13 reference genome have the potential to reveal novel gene bodies and transcript isoforms that were missed in previous studies. These methods can provide a more complete picture of the transcriptomic landscape of diseases, including Alzheimer’s disease—hopefully generating information with potential to help inform future treatment and/or early diagnostic efforts.
PFF induced striatal neurodegeneration model for preclinical proof of concept studies targeting alpha‐synuclein pathology
Authors: Cornelissen Tom
Published: December 2022

Background

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder with more than half of the patients developing dementia about 10 years later, and is characterized by the accumulation of alpha‐synuclein protein aggregates in the PD brain. These inclusions, also called Lewy bodies, accompanied with the degeneration of dopaminergic neurons are the neuropathological hallmark of this devastating incurable disease. Currently a lot of effort is put in studying the involvement of different forms of alpha‐synuclein, i.e. monomeric, oligomeric, fibrillar and aggregated forms or different post translational modifications of the protein, and their contribution to disease progression. Targeting alpha‐synuclein might thus be of potential therapeutic value. Since the research field lacks good and consistent animal models for preclinical research, we’ve set up a mouse model based on the striatal administration of sonicated preformed fibrils (PFF).

Method

In brief, we performed unilateral stereotactical injections in the dorsal striatum of young wild type mice with sonicated PFF’s (n = 8/group). PFF injected mice were sacrificed after 5, 9 and 13 weeks, a control group of vehicle injected mice (n = 7) was sacrificed after 9 weeks. Phosphorylated alpha‐synuclein (pSer129) seed and spread and dopaminergic neurodegeneration was visualized by IHC in different brain regions both ipsilateral and contralateral.

Result

Phosphorylated alpha‐synuclein (pSer129) positive inclusions were shown to be present in Striatum, substantia nigra (SN) and amygdala in the ipsilateral hemisphere already after 5 weeks, indicating clear spreading of pathology. Interestingly, in the contralateral hemisphere we were able to detect clear pSer129 alpha‐synuclein in the amygdala and striatum 5 and 9 weeks after injection respectively, demonstrating the progressive nature of this model. To assess whether the observed pathology also affected the dopaminergic circuitry we quantified the loss of synaptic tyrosine hydroxylase positive terminals in the striatum and found a significant decrease already 5 weeks after PFF administration.

Conclusion

This alpha‐synuclein preformed fibril based model, which shows clear progressive seed and spread pathology and a clear decrease in dopaminergic nerve terminals in the striatum, can be of great importance to the research field to assess in vivo therapeutic interventions based on targeting alpha‐synuclein pathology.
Age‐dependent effects of the p75 neurotrophin receptor modulator LM11A‐31 on Alzheimer’s disease biomarkers in a 26‐week safety and exploratory endpoint trial
Authors: Shanks Hayley R. C. , Börjesson‐Hanson Anne , Windisch Manfred , Massa Stephen M. , Longo Frank M. , Schmitz Taylor W.
Published: December 2022

Background

The p75 neurotrophin receptor (p75NTR) modulates pro‐ and anti‐apoptotic pathways as well as neurite and neuritic spine integrity. This receptor is expressed in cells vulnerable to aging and disease, including basal forebrain cholinergic neurons and hippocampal pyramidal neurons. It is also expressed by glial cells under pathological conditions. Pharmacological modulation of the p75NTR with LM11A‐31 alters both age‐ and disease‐related neuronal dysfunction. For example, LM11A‐31 reverses neuritic pathology in aged mice and reduces amyloid‐induced tau phosphorylation in mouse models of Alzheimer’s disease (AD). In this proof‐of‐concept study, we examined the effects of LM11A‐31 treatment on longitudinal neuroimaging and CSF biomarkers in humans with mild to moderate Alzheimer’s disease. Based on our preclinical work, we hypothesized that age and disease may interact to predict response to LM11A‐31 treatment in humans. Therefore, we additionally conducted subgroup analyses of drug effect in older and younger individuals.

Method

Participants with mild to moderate AD (MMSE score = 18‐26; age 55‐85 years) were enrolled in a 26‐week placebo‐controlled phase 2a safety and exploratory endpoint trial of LM11A‐31. Exploratory outcome measures included structural MRI, CSF AD core biomarkers, and CSF biomarkers related to pathological processes affected in mouse studies including synaptic integrity and inflammation. For placebo and drug, age subgroups were defined using a median‐split: younger (<72 years) and older (> = 72 years).

Result

Whole brain structural MRI analyses revealed that 26‐week treatment with LM11A‐31 reduced longitudinal grey matter degeneration in AD‐vulnerable brain regions including the inferior temporal gyrus, insula, frontal operculum and retrosplenial cortex. Furthermore, drug treatment, compared to placebo, prevented longitudinal increases of CSF tau, the presynaptic biomarker SNAP25, and the inflammatory biomarker YKL‐40. Median split analyses demonstrated that drug effects for structural MRI and CSF measures were consistently stronger in younger individuals.

Conclusion

This investigation highlights that biomarkers may demonstrate age‐dependency in response to therapeutic interventions in the context of mild‐moderate AD. Our results may inform biomarker selection and design of future studies of LM11A‐31 in human AD.
An M1/sigma‐1 receptor agonist prevents cognitive deficits, reduces amyloid plaques and neuroinflammation in a transgenic rat model of Alzheimer’s amyloid pathology.
Authors: Orciani Chiara , Carmo Sonia Do , Foret Morgan K , Hall Hélène , Bonomo Quentin , Lavagna Agustina , Huang Chunwei , Cuello Claudio A
Published: December 2022

Background

Acetylcholinesterase inhibitors represent four out of six drugs for treating Alzheimer’s disease (AD), with time‐limited efficacy likely due to the progressive loss of cholinergic neurons. The selective allosteric M1 muscarinic and sigma‐1 receptor agonist Anavex 3‐71 (aka AF710B) [1] takes advantage of the fact that acetylcholine postsynaptic M1 muscarinic brain receptor levels remain unchanged in AD. Previously, Anavex 3‐71 treatment attenuated AD hallmarks in McGill‐R‐Thy1‐APP transgenic rats when administered at advanced stages of the AD‐like pathology [2]. However, preventive strategies instead of late treatment should be more effective in AD. Therefore, we tested whether Anavex 3‐71 administration during early amyloid pathology stages could prevent cognitive impairment, plaque deposition and neuroinflammation.

Method

Pre‐plaque, seven‐month‐old McGill‐R‐Thy1‐APP rats were subjected to daily oral administration of Anavex 3‐71 (10 µg/kg) for seven months. After one month of drug interruption (wash‐out), we performed Novel Object Recognition (NOR), Morris Water Maze (MWM) and Social Preference (SP) behavioural tests. Subsequently, brains were extracted, fixed and analyzed by histochemistry and immunohistochemistry.

Result

McGill‐APP rats had deficits in discriminating the novel object in the NOR and locating the hidden platform in the MWM compared to wild‐type littermates. Anavex 3‐71 restored the abilities of McGill‐APP rats in the NOR task to wild‐type levels and partially rescued the deficits in the MWM. In the SP task, Anavex 3‐71‐treated McGill‐APP rats exhibited diminished deficits in SP interaction time with a “stranger rat”. Treatment significantly reduced the number of mature Thioflavin‐S positive plaques in the subiculum compared to vehicle‐treated McGill‐APP rats and diminished the number of diffuse plaques in the cortex and hippocampus. Furthermore, Anavex 3‐71 treatment significantly reduced microglia and astrocyte recruitment towards CA1 hippocampal Aβ‐burdened neurons compared to untreated McGill‐APP rats.

Conclusion

The long‐lasting effect of Anavex 3‐71 in preventing cognitive decline of McGill‐R‐Thy1‐APP rats, even after a wash‐out period would suggest some preventative, disease‐modifying, properties of the compound over the AD‐like amyloid pathology. This is supported by the attenuation of extracellular Aβ deposition and reduced glial cell recruitment towards hippocampal neurons. [1] Fisher et al., 2016; Neurodegenerative Diseases. https://doi.org/10.1159/000440864 [2] Hall et al., 2018; Alzheimer’s & Dementia. https://doi.org/10.1016/j.jalz.2017.11.009
Clinical Profiles of Persons Who Progress to Cognitive Impairment in the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial
Authors: Giraldo‐Chica Margarita , Acosta‐Baena Natalia , Espinosa Alejandro , Ramos Claudia , Langbaum Jessica B. , Sink Kaycee M. , Tariot Pierre N. , Reiman Eric M. , Lopera Francisco , Ríos‐Romenets Silvia
Published: December 2022

Background

In Colombia, 13 pathogenic variants of presenilin 1 (PSEN1) causing Autosomal Dominant Alzheimer’s Disease (ADAD) have been identified. Some cases have atypical presentations, with variability in the age of onset and course of the disease. We characterized clinical profiles of cognitively unimpaired PSEN1 E280A mutation carriers who progress to MCI or dementia in the API ADAD Colombia Trial.

Method

The API ADAD Colombia Trial enrolled 252 cognitively unimpaired 30–60 year‐old participants into a 5‐8‐year double‐blind placebo controlled randomized prevention trial with a common close design. About 1/3 of participants were PSEN1 E280A mutation carriers who were randomized to the investigational anti‐oligomeric amyloid‐β antibody therapy crenezumab, 1/3 were mutation carriers who were randomized to placebo, and 1/3 were non‐carriers from the same kindred who were randomized to placebo. Trial results are pending. We used standardized procedures to blindly assess clinical features of participants who progressed to MCI and/or dementia during the trial, reviewed by an independent progression adjudication committee (PAC), to confirm the first instance of clinical progression.

Result

During the trial 45 participants had an initial progression to MCI due to AD and 2 to dementia due to AD confirmed by the PAC. Among the 45 adjudicated with MCI due to AD, 32 subsequently progressed to dementia (30 due to AD and 2 due to other causes as determined by the site clinicians by consensus). The mean age onset of MCI was 45 (range 36–60 years) and of dementia was 47 (range 36–62 years). Three participants developed dementia before 40 years and one participant at 62 years. At the time of MCI, 43 participants had a predominantly amnesic profile, one had a predominantly behavioral disinhibition, and one had a Capgras syndrome, severe aggression and myoclonus. One participant developed severe global aphasia two years after the onset of dementia; two of the participant’s first‐degree relatives had language impairment in conjunction with MCI; one developed primary progressive logopenic aphasia.

Conclusion

Some persons with ADAD have an atypical clinical presentation. Additional studies are needed to clarify the biological changes, genetic/environmental risk factors, clinical course and response to treatment in these individuals.
A Phase 3 Clinical Trial Protocol to Evaluate the Efficacy and Safety of NA‐831 in Subjects with Early Onset of Alzheimer’s Disease
Authors: Tran Lloyd , Vu Fern , Kurkinen Markku
Published: December 2022

Background

This phase 3 study consists of a Core and Open Label Extension (OLE) Phase in 465 participants with Early Alzheimer’s Disease (EAD), and is being conducted to evaluate the efficacy and safety of NA‐ 831. The Core is a 52‐week treatment, multicenter, double blind, placebo controlled parallel group study.

Method

Core Study: Participants will receive one capsule of 30 milligram (mg) NA‐831 orally once a day in the morning. The core study will be double blinded. Placebo Comparator: The core study will be double blinded. Experimental: Open Label Extension Phase: Participants completing the core study will receive one 30 milligram (mg) NA‐31 capsule orally once a day in the morning.

Result

Key Outcome Measures:

1. Core Study: Change from Baseline in the Clinical Dementia Rating and Sum of Boxes (CDR‐SB) Score at 48 Weeks [ Time Frame: Baseline, Week 52]

2.Open‐Label Extension Phase: Number of Participants With Treatment‐Emergent Adverse Events (AEs) [ Time Frame: Up to Week 52 of Extension Phase] Secondary Outcome Measures: Cognition‐13 (ADAS‐Cog‐13) at Weeks 24, 52 [ Time Frame: Baseline, Week 24, Week 52 of Extension Phase] CORE STUDY: Mild cognitive impairment due to AD or mild AD dementia including 1. MMSE score equal to or greater than 24

3. CDR global score of 0.5 3. CDR Memory Box score of 0.5 or greater

Conclusion

The Phase 3 clinical trial of NA‐831 is being conducted in multicenters in the US and several countries. The details of the Phase 3 methodology and protocol will be presented and discussed.