bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the Effects of Burden on Alzheimer’s Patients’ Caregivers: A Comprehensive Review
Authors: Karur Prasanna , Shah Anjali , Marivada Snigdha , Patel Saajan , Khanna Deepesh
Published: December 2023

Background

Although Alzheimer’s disease (AD) care is a heavily researched subject, caregiver burden is often overlooked. Caregiver burden may hinder care for those with AD. The objective is to assess caregiver burden in respect to sleep patterns, depression, and gender identity.

Method

A comprehensive review of effects of caregiver burden for AD patients was conducted using databases such as PubMed and Google Scholar. PRISMA guidelines were followed. Keywords “caregiver burden,” “Alzheimer’s,” and “dementia” were paired with “sleep disturbance,” “depression,” and “gender” to find relevant articles. All searches were performed by the authors and re‐assessed for accuracy. Searches were restricted to publications from 2008‐2022. Eligible studies were excluded if caregiver burden was associated with diseases other than AD. Inclusion criteria consisted of AD caregivers from homes, nursing homes, and hospitals. Papers in the review were not restricted to the US population.

Result

According to literature, AD caregivers reported sleep disturbances, with 58% reporting poor sleep quality, ⅔ being disturbed in the middle of their sleep, and 47% being woken up several times throughout the night1. Studies indicated that those caregivers with worse sleep quality had more depressive symptoms. Most studies showed a positive association between depression and AD caregivers. One article indicated that caregivers demonstrated the following depressive attributes: poor ability to take care of themselves, ignorance of basic physical and emotional needs, and low self‐care2. Findings show that female caregivers experienced a higher level of burden compared to male caregivers, specifically in regard to time dependence, development, physical, and social burdens.

Conclusion

Findings suggest that the quality of sleep is decreased, depressive and other neuropsychiatric symptoms were associated with caregiver burden, and females were more affected by caregiver burden than males. We recommend raising awareness and providing resources that may reduce this burden for AD caregivers.

1. Creese, J., Bédard, M., Brazil, K., & Chambers, L. (2008). Sleep disturbances in spousal caregivers of individuals with Alzheimer’s disease. International Psychogeriatrics, 20(1), 149‐161. https://doi.org/10.1017/S1041610207005339

2. Vespa, A., Spatuzzi, R., Fabbietti, P., Penna, M., & Giulietti, M. V. (2021). Association between care burden, depression and personality traits in Alzheimer’s caregiver: A pilot study. PloS One, 16(9), e0251813. https://doi.org/10.1371/journal.pone.0251813
Cardiometabolic disease, cognitive decline, and structural brain differences in mid‐ and late‐life: a large population‐based cohort study
Authors: Dove Abigail , Guo Jie , Wang Jiao , Sakakibara Sakura , Xu Weili
Published: December 2023

Background

The impact of cardiometabolic diseases (CMDs; including type 2 diabetes [T2D], heart disease [HD], and stroke) on cognitive trajectories and brain structural changes across the life course is unclear. We aimed to explore the association of patterns of co‐morbid CMDs with cognitive decline and structural brain MRI measures in mid‐ vs. late‐ life.

Method

Within the UK Biobank, 46,562 dementia‐free participants aged 40‐70 were followed for 9 years. Baseline CMDs were ascertained medical records. A battery of 5 cognitive tests was administered at baseline and follow‐up and used to derive global and domain‐specific cognitive function scores. A subsample (n = 39,353) underwent brain magnetic resonance imaging (MRI) scans at the follow‐up examination. Volumes of total brain, white matter, grey matter, hippocampus, and white matter hyperintensities (TBV, WMV, GMV, HV, and WMHV) were assessed. Data were analyzed using multivariate adjusted mixed‐effects models and linear regression.

Result

At baseline, 3,437 (7.4%) participants had 1 CMD and 297 (0.6%) had ≥2. In mixed‐effects models, the presence of any CMD was related to a steeper decline in global cognitive function (β [95% confidence interval]: ‐0.005 [‐0.008, ‐0.003]) as well as working memory (‐0.024 [‐0.033, ‐0.014]), visual declarative memory (‐0.004 [‐0.007, ‐0.001]), and processing speed (‐0.002 [‐0.002, ‐0.001]), especially for those with CMD profiles involving T2D and/or HD. In stratified analysis by age (mid‐ [<60] vs. late‐ [≥60] life), CMDs were related to a decline in only processing speed in mid‐life, while in late‐life, CMDs were additionally related to a decline in verbal/numeric reasoning. In linear regression, people with CMDs had significantly lower TBV (‐0.15 [‐0.18, ‐0.12]), GMV (‐0.17 [‐0.20, ‐0.14]), WMV (‐0.11 [‐0.14, ‐0.08]), HV (‐0.14 [‐0.18, ‐0.11]) and significantly higher WMH (0.05 [0.02, 0.09]), and this was exacerbated among people with ≥2 CMDs compared to 1 CMD. Similar results were observed in both mid‐ and late‐life.

Conclusion

The presence of CMDs is associated global/domain‐specific cognitive decline and brain MRI measures involving neurodegenerative and vascular markers in both mid‐ and late‐ life. Our findings highlight the need for the effective management of CMDs in mid‐life for the prevention of dementing disorders in late‐life.
The feasibility and preliminary efficacy of a novel, online culturally tailored psychoeducation course for Black dementia caregivers
Authors: Alexander Karah L , Cave Nkosi , Oliver Sloan , Epps Fayron
Published: December 2023

Background

Many psychoeducation interventions utilizing different distant learning modalities to engage caregivers have been effective in enhancing caregiving mastery, but few programs have been specifically adapted to develop mastery in Black caregivers (Gallagher‐Thompson & Coon, 2007; Pinquart & Sörensen, 2006). The purpose of this study was to assess the feasibility and preliminary efficacy of the novel Caregiving while Black psychoeducation course (CWB). CWB was co‐produced by Black caregivers, persons living with dementia, and healthcare professionals. Caregivers from across the United States participated in the pilot study and engaged in ∼10 hours of asynchronous, online content related to healthcare system navigation, managing home life, and caregiver self‐care topics.

Method

Using quantitative and qualitative methods, caregivers were allotted 10‐weeks to complete the course and were quantitatively assessed on burden, depression, anxiety, and mastery at baseline, midpoint, and end of study. Caregivers then participated in an optional qualitative assessment (semi‐structured interview) of their experiences with course engagement. Descriptive statistics and t‐tests were used for quantitative data analysis and qualitative data were thematically analyzed.

Result

Of the 75 caregivers enrolled, 31 were withdrawn to reasons including personal illness, death of care recipient, and reporting being too busy. Sixty‐four caregivers attempted the course with 32 completing the course within the timeframe. Quantitative data revealed significant improvement in caregiver depression, burden, and role strain. Caregiver mastery from baseline to completion increased 0.42 points. Twenty‐nine caregivers participated in a qualitative assessment which produced 5 overarching themes: Comfortability with a Culturally Tailored Course, Experiences Navigating the Course Platform; Utility of Course Resources; Time as a Barrier and Facilitator; Familial and Community Engagement.

Conclusion

Findings confirmed CWB’s ability to improve Black caregivers’ emotional well‐being and sense of confidence and mastery in their caregiving role. Caregivers expressed their appreciation of a culturally tailored course to address their needs and greatly utilized the external resources the course offered. However, time and complexities with the course’s online platform served as a barrier for many, to optimize engagement with and even finishing the course. Study findings will help inform and fuel the success of the next iteration of the Caregiving while Black Course.
UPREGULATING ABCA1‐MEDIATED CHOLESTEROL TRANSPORTATION BY CS6253 – OPPORTUNITY FOR CONVENIENT SC ROUTE OF ADMINISTRATION
Authors: Johansson Jan O. , Winblad Bengt , Michaelson Daniel M , Zetterberg Henrik , Cummings Jeffrey L. , Yassine Hussein N.
Published: December 2023

Background

The ATP‐binding cassette transporter A1 (ABCA1) is a validated target for AD and upregulation has therapeutic potential in APOE4‐associated AD. The apoE4 protein compared to E2/E3 has impaired interaction with the ABCA1 transporter protein, affecting cholesterol homeostasis in the brain, causing dementia and hemorrhage. CS6253 is an ABCA1‐agonist that in monkey’s has shown safety and increase in Ab42/40‐ratio. A phase 1 SAD‐MAD with CS6253 administered IV was initiated. Here we describe translational efforts for transitioning from IV to SC route‐of‐administration.

Method

The Phase 1 is initiated with SAD:

In 4‐6 cohorts of 8 subjects (6 active: 2 placebo) CS6253 starting with 1 mg/kg will be administered IV and plasma and CSF collected simultaneously over 24 hours to assess PK and response markers, and, MAD: In 3‐4 cohorts of 8 subjects (6 active: 2 placebo) CS6253 will be administered to elderly stratified for sex and APOE4 status.

Using the identical CS6253 drug product, a GLP local‐tolerance study in rats was conducted to support up to 30 days SC administration in humans. Rat groups of n = 12 received PBS‐control and 7.5, 25 and 75 mg/kg CS6253 SC every other day, 7 times. PK is analyzed by LC‐MS following first and 7th/last dose.

Result

Bodyweight: Treated animals gained weight throughout the study at a comparable rate to control; no Test Article(TA)‐related variations identified.

Clinical Signs: No TA‐related observations were noted, all animals remained in good condition until the end of dosing and end of recovery.

Food consumption: No TA‐related effects on food consumption, all means were comparable to controls.

Gross Pathology: No gross lesions were observed for terminal and recovery animals.

Human Phase 1 SAD results are expected late summer of 2023 and human MAD data late fall of 2023 and with clearing local‐tolerance toxicology the CS6253 program can transition from IV to SC route‐of‐administration.

Conclusion

The ABCA1 agonist CS6253 has therapeutic potential for APOE4‐associated AD. Safety, PK and biomarker efficacy is being assessed in a Phase 1 study. The SC local tolerance study opens up the potential to self‐administer CS6253 SC for optimal convenience and compliance.
Tunneling nanotubes at the microglia‐neuron interface in neuroinflammation and Alzheimer’s disease
Authors: Zaccard Colleen R , Parnell Euan , Gippo Isabel , Geula Changiz , Penzes Peter
Published: December 2023

Background

Brain‐resident innate immune cells termed microglia can mediate synapse formation and plasticity, but become dysregulated in Alzheimer’s disease (AD), contributing to chronic neuroinflammation and synapse loss (Wu, Dissing‐Olesen et al. 2015, Hong, Beja‐Glasser et al. 2016). Yet, the mechanisms underlying direct microglia‐neuron interactions are poorly defined. Pro‐inflammatory signals can induce extremely long, thin, membranous connections, i.e., tunneling nanotubes (TNTs), in peripheral innate immune cells (Zaccard, Rinaldo et al. 2016). TNTs have been observed in various cell types and can support high‐speed, cell‐cell trafficking of diverse cytoplasmic and membrane‐bound cargoes. Herein, we explore the role of TNTs in microglia‐neuron communication during neuroinflammation and AD.

Method

We established a co‐culture model of human induced excitatory neurons (iENs) and postmortem elderly adult human microglia. Microglia‐tropic adeno‐associated virus vectors encoding plasma membrane‐targeted tdTomato fluorophores were utilized to label microglia and emerging TNTs. We treated co‐cultures with pro‐inflammatory factors, i.e., oligomeric amyloid β (Aβ) and interferon‐gamma, or anti‐inflammatory factors for 24 hours, and utilized our recently developed enhanced resolution confocal microscopy technique to assess TNTs.

Result

The number of TNT‐positive microglia and number of TNTs per microglia were increased in live human iEN‐microglia co‐cultures under AD‐relevant pro‐inflammatory conditions compared to anti‐inflammatory or control conditions. Additionally, TNT length and the percentage of TNTs contacting neuronal axons or dendrites were significantly increased under pro‐inflammatory conditions. We used time‐lapse enhanced resolution imaging to capture microglial TNTs interacting with spine‐like dendritic protrusions, which extended finer spinule‐like protrusions. Finally, we visualized direct, rapid, cell‐cell transfer of oligomeric Aβ and enhanced localization of oligomeric Aβ to TNTs under pro‐inflammatory conditions in microglia mono‐cultures.

Conclusion

Our results in human iEN‐microglia co‐cultures indicate that an AD‐relevant, pro‐inflammatory micro‐environment increases microglial TNT formation and TNT‐driven interactions with neuronal axons, dendrites, and dendritic protrusions. TNTs can provide additional contact points and extend the reach of microglia, facilitating communication with distant target microglia or sub‐neuronal elements. During chronic neuroinflammation in aging and AD, TNT over‐expression likely increases microglia‐synapse interactions and supports rapid, cell‐cell spread of Aβ. Hence, TNTs may contribute to AD progression and could represent a new target for therapeutic intervention in neurodegenerative disorders.
Which Mild Behavioral Impairment‐Checklist (MBI‐C) items discriminate between cognitive diagnoses at baseline and follow‐up? Results from the Compostela Ageing Study (CompAS)
Authors: Mallo Sabela Carme , Real‐Deus Eulogio , Pérez‐Blanco Lucía , Felpete Alba , Campos‐Magdaleno Maria , Facal David , Nieto‐Vieites Ana , Pereiro Arturo X
Published: December 2023

Background

The Mild Behavioral Impairment Checklist (MBI‐C) is a 34 Neuropsychiatric Symptoms (NPS) checklist for the evaluation of pre‐dementia states. Our aim was to analyze which MBI‐C symptoms could best discriminate between participants with different cognitive outcomes both at baseline and at diagnosis time (after 50‐75 months).

Method

A total of 179 participants from the Compostela Aging Study (CompAS) were included in the analyses, 108 identified as Subjective Cognitive Complainers (SCC), 47 diagnosed as Mild Cognitive Impairment (MCI) and 24 diagnosed as dementia. NPS were assessed using the validated Spanish version of the MBI‐C (Mallo et al., 2018) at baseline and 50‐75 months follow‐up. Discriminant analyses were carried out at baseline and follow‐up, being the dependent variable the diagnosis at the follow‐up and the independent variable the MBI‐C scores.

Result

The results of the discriminant analysis at baseline indicated a poor adjustment of the model to the data (Wilk’s lambda = .821; p<.001). At baseline, three items (item 9 “discouraged”, 22 “hoard objects”, and 19 “stubborn/rigid”) discriminate 65% of cases, mostly SCCs (97.2%) (Table 1).

The results of the discriminant analysis at follow‐up indicated a much better adjustment of the model to the data (Wilk’s lambda = .468; p<.001) (Table 1).

The variance was explained almost exclusively by the first function obtained (53%) while the second only reached 7%. At follow‐up, seven items discriminate between groups (item 4 “unmotivated”, 25 “less sensible”, 26 “talk to strangers”, 21 “food no tasty”, 24 “control difficulties”, 5 “less emotional”, 28 “no social judgement”). These items correctly discriminated the SCC (99%) and the 66.7% of dementia patients, but only 6.8% of the MCI (Figure 1).

Conclusion

Model fit at baseline was poor, and almost exclusively discriminate SCC. The discrimination power increased as the MBI‐C measure were close to the diagnosis, especially for dementia.

Distal prediction of dementia nor predementia states using NPS was not successful though some MBI‐C items showed slight better performance at baseline than in follow‐up.
Identification of diverse pathological Tau forms in the retina of MCI and AD patients
Authors: Shi Haoshen , Mirzaei Nazanin , Davis Miyah R , Koronyo Yosef , Fuchs Dieu‐Trang , Sheyn Julia , Jallow Ousman , Kramerov Andrei A , Ljubimov Alexander V , Kayed Rakez , Miller Carol A , Black Keith L , Koronyo‐Hamaoui Maya
Published: December 2023

Background

Neurofibrillary tangles (NFTs) formed by abnormal accumulation of the microtubule‐associated protein tau is a key pathological hallmark of Alzheimer’s disease (AD). Presence of abnormal tau forms has been shown to correlate with the degree of neurodegeneration and cognitive decline. A few studies have previously described increases of hyperphosphorylated tau (pTau) in postmortem retinas of AD patients. However, it remains largely unknown if these and other abnormal tau forms are present in the retina of mild cognitively impaired (MCI) and AD patients and their relations with brain pathology is undefined.

Method

Fifty‐three postmortem human eyes and thirty‐nine paired brains were obtained for this study. Retinas were isolated from 22 AD and 10 MCI patients, and 21 age‐ and sex‐matched cognitively normal (CN) controls. Retinal cross‐sections spanning along ora serrata to optic disc were prepared from four pre‐defined quadrants: superiortemporal, temporalinferior, inferiornasal, and nasalsuperior. Histological analyses were conducted by immunostaining brain and retinal cross‐sections by specific antibodies for NFTs and oligomeric Tau. pTau were explored by using antibodies to detect pS396+, AT8+ (Ser202, Thr205) and AT100+ (Thr212, Ser214). Quantification of tauopathy forms were measured by stereological examination then correlated with the neuropathological reports of these patients.

Result

Our examination by both immunofluorescence and peroxidase‐based staining identified the presence of NFTs and novel oligomeric tau forms in AD‐afflicted retina. Stereological analyses of retinal cross‐sections and brains demonstrated a significant upregulation of NFTs and AT8+, pS396+ pTau forms in retinas from MCI patients compared to CN controls; exacerbated tauopathy was found in the retina of AD patients. NFTs and pTau were more frequent in the peripheral retina compared with the central retina. We found intense staining patterns of tauopathy along the synaptic‐rich regions (OPL and IPL). Preliminary correlation analysis suggest significant associations between retinal pS396+ pTau burden and cerebral pathologies including NFT burden, neuropil threads, and cognitive deficit.

Conclusion

This study identifies NFTs in the AD retina and demonstrates the accumulation of both soluble and fibrillar forms of tauopathy in the retina of MCI and AD patients. Future retinal imaging of tauopathy may allow a noninvasive means to screen and monitor AD progression.
The performance of AlzoSure® Predict in stratifying the risk to experience a significant cognitive deterioration, due to Alzheimer’s Disease
Authors: Agus Shmuel , Piccirella Simona , Van Neste Leander , Fowler Christopher J , Masters Colin L , Fripp Jurgen , Doecke James D , Uberti Daniela , Kinnon Paul
Published: December 2023

Background

Treatments for patients with Alzheimer’s Disease (AD) are now available, and are associated with certain risks. There is an increased need from providers, to have tools that will aid in clinical decision‐making.

Method

The AlzoSure® Predict test, is an IP‐LC‐MS/MS based method, to quantify the AZ284® peptide of an unfolded variant of the p53 protein (U‐p53AZ).

A dataset from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, with 479 participants, aged 60‐85, 237 being cognitively normal (CN), 98 with minimal cognitive impairment (MCI), 141 with dementia due to AD (ADD), and 3 with non‐AD dementia (OD), was used to validate the performance of AlzoSure® Predict to identify the risk individuals, to experience a significant cognitive deterioration (CN to MCI or ADD and MCI to ADD) and to stratify them according to the time frame, during which, this will occur (6 or 2 years).

Result

316 participants had a follow up of up to 6 years, and 294 had a follow up of up to 2 years.

The performance of AlzoSure® Predict, as measured by AUC, is high, regardless of the follow‐up time frame. For prediction of deterioration within 6 years, the obtained AUC is 0.9842 with DeLong 95% CI: 0.9727‐0.9956 (68 case, who experienced a deterioration, and 248 controls), ho didn’t and for prediction of deterioration within 24 months, it is 0.9891, with DeLong 95% CI: 0.9789‐0.9994 (46 cases, and 248 controls).

The cut‐off values of AlzoSure® Predict are defined to stratify individuals, at the time of testing, according to the time frame, during which they may experience a significant cognitive deterioration.

AlzoSure® Predict showed high performance to identify rapid progressors to AD within 2 y, with a PPV/ NPV >90%, Sens>80%, and Spec>95%

Conclusion

AlzoSure® Predict has the capability to identify individuals, who are at risk to experience a significant cognitive deterioration, and stratify this risk according to the time frame, even in a period within 2 years, during which this deterioration will occur.

AlzoSure® Predict can become a tool, to strengthen a personalized clinical decision‐making, with improved precision, to be used by providers, who care for patients with AD.
Gut Microbiome Predicts Cognitive Function and Depressive Symptoms in Late Life
Authors: Kolobaric Antonija , Andreescu Carmen , Jašarević Eldin , Hong Chang Hyung , Roh Hyun Woong , Kim Yoon Keun , Aizenstein Howard J , Karim Helmet T. , Son Sang Joon
Published: December 2023

Background

Depressive symptoms in older adults with cognitive impairment increase the likelihood of progression to dementia. Current mood and cognitive function associate with microbial composition, but the extent to which the microbiome may predict clinical trajectory is unknown. We investigated the capacity of the gut microbiome to reflect current and predict future cognitive function and depressive symptoms.

Method

Clinical assessments and stool samples were collected from 268 participants with varying cognitive function and depressive symptoms. Seventy participants underwent a 2‐year follow‐up. Microbial community diversity, structure, and composition was assessed using high‐resolution 16S rRNA marker gene sequencing (Figure 1). We implemented multiple linear regression to characterize the relationship between microbiome composition, current cognitive impairment, and depressive symptoms. We leveraged elastic net regression to discover microbial community metrics and microbial functional pathways that reflect current or predict future cognitive function and depressive symptoms (Figure 2).

Result

Greater microbial community diversity, indicating a higher number and even distribution of species within a community, was associated with worse current cognitive function in the sample, as well as greater depression severity in participants not on antidepressants. Poor current cognitive function was associated with lower relative abundance of Bifidobacterium. On a functional level, we demonstrate an association between greater GABA degradation and greater current depression severity (Figure 2). Future cognitive decline was associated with lower cognitive function and increased anxiety at baseline. Future cognitive decline was also associated with decreased relative abundance of Firmicutes and Intestinibacter, higher glutamate degradation, and higher baseline histamine synthesis (Figure 2). Future increase in depressive symptoms was associated with higher baseline depression and anxiety, lower cognitive function, and lower relative abundance of Bacteroidota (Figure 2).

Conclusion

We display utility in microbiome composition for predicting future cognitive function and depressive symptoms in late life. Our results suggest the gut microbiome may present a noninvasive prognostic for cognitive and psychiatric states. Advancing our understanding of gut‐brain axis in aging may inform the development of neurobiologically driven interventions to ameliorate cognitive decline and depressive symptoms in late life.
Hispanic/Latino perspectives about participation in online recruitment registries for research
Authors: Duran Edwin , Moya‐Fajardo Ciria , Meza Novelle , Grill Joshua D , Salazar Christian R.
Published: December 2023

Background

Online recruitment registries have emerged as a novel approach for accelerating enrollment of participants in Alzheimer’s disease (AD) research. While investigators may benefit from having access to a large research‐ready and often prescreened population, older Hispanic/Latino adults enroll less frequently in online recruitment registries, particularly for AD. Using qualitative data from focus groups, we elicited perspectives from community dwelling older Hispanics/Latinos about barriers and facilitators to participation in online registries that recruit to AD research studies.

Method

We conducted 4 focus groups via Zoom in May 2022 and enrolled a total of 15 older Hispanic/Latino adults aged 50+ years who participated in the University of California, Irvine Consent‐to‐Contact (C2C) registry. The C2C is a local online recruitment registry that enrolls individuals from Orange County (OC), California and collects minimal data for the purpose of better matching participants to recruiting studies. We used a semi‐structured interview guide to assess Hispanic participants’ perceptions and experiences about AD research, motivators and barriers to enrolling into an online recruitment registry and suggestions for framing messages to improve enrollment.

Result

Hispanic/Latino participants were predominately female (60%), US born (80%), college educated (80%) and had a mean age of 60. Reflexive thematic analysis identified 3 emergent themes: (1) being personally affected by AD as a driving factor in participants’ desire to participate; (2) a lack of digital literacy and access to digital devices as a barrier to enrollment; and (3) framing messages that are culturally tailored and aimed at reducing fear towards research.

Conclusion

Understanding the factors that drive decisions to enroll in online registries among Hispanics/Latinos will be crucial for the development of interventions to improve participation. Our preliminary results highlight key concerns among older Hispanics/ Latinos already in registries. Additional focus groups will include other key stakeolders from Hispanic/Latino communities in OC to compare findings.
Development of Potent and Selective Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 2 for the Potential Treatment of Alzheimer’s Disease
Authors: Coleman Jeremy S , Capstick Rory A , Rathnayake Upendra A , Parr Lauren , Chang Sichen , Thompson Analisa D , Qi Aidong , Niswender Colleen M , Boutaud Olivier , Plumley Hyekyung , Jones Carrie K , Engers Darren , Lindsley Craig W
Published: December 2023

Background

The metabotropic glutamate receptor 2 (mGluR2) is a group II mGluR that binds glutamate and utilizes Gi/o signaling within the central nervous system (CNS) to modulate synaptic transmission and neuronal excitation.1 The alteration of basal glutamate signaling has been implicated in a variety of neurodegenerative diseases including Alzheimer’s disease (AD).2 mGluR2 has been found to be overexpressed in the hippocampal neurons of AD patients and receptor overactivation has been shown to induce plaque formation in in vitro AD models.3, 4 Thus, the utilization of a mGluR2 negative allosteric modulator (NAM) may prevent neurodegeneration. The utility of mGluR2 NAMs for neurodegenerative diseases remains unclear due to the lack of mGluR selectivity of historical compounds.

1. Niswender, C.M. and P.J. Conn, Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annual review of pharmacology and toxicology, 2010. 50: p. 295‐322.

2. Li, S.H., K.S. Abd‐Elrahman, and S.S.G. Ferguson, Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases. Pharmacology & Therapeutics, 2022. 239: p. 108275.

3. Lee, H.‐g., et al., Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer’s disease. Acta Neuropathologica, 2004. 107(4): p. 365‐371.

4. Caraci, F., et al., Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer’s disease: selective activation of mGlu2 receptors amplifies beta‐amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective. Mol Pharmacol, 2011. 79(3): p. 618‐26.

Method

Novel mGluR2 NAMs were synthesized using an iterative library synthetic approach to improve potency, selectivity, and provide an overall sufficient drug metabolism/pharmacokinetics (DMPK) profile. Compound potency (IC50) and selectivity were evaluated in an in vitro GIRK cell‐based T1 flux assay expressing mGluR2 or mGluR3 receptors. Lead compounds were tested in in vitro plasma protein binding assays and rat in vitro and in vivo clearance values were obtained.

Result

The successful discovery and development of a potent and selective mGluR2 NAM as an in vivo tool compound to elucidate the biological effects associated with mGluR2 antagonism was achieved.

Conclusion

mGluR2 NAMs may be useful therapeutic agents for the potential treatment of AD and other neurodegenerative diseases.
Feasibility and acceptability of automated cognitive assessment over the telephone in the SpeAK study
Authors: Hunter Matthew B , Gregory Sarah , Harrison John E , Jenkins Natalie D , König Alexandra , Linz Nicklas , Luz Saturnino , Mallick Elisa , Pullen Hannah , Welstead Miles , Tröger Johannes , Ritchie Craig W
Published: December 2023

Background

There is growing interest in the development of speech markers as novel, non‐invasive biomarkers of early Alzheimer’s disease (AD). Before including such speech assessments in clinical trials, the technology must be tested to confirm feasibility of administration and acceptability with the target population to ensure future engagement. This study aimed to assess feasibility and acceptability in an at‐risk population receiving automated administration of cognitive tasks over the telephone during the Speech on the Phone Assessment (SPeAk) study [35]. A second goal of the study was to assess participant acceptability of receiving cognitive test results ‐ an important consideration for psychological safety.

Method

Participants (n = 68, mean age 70.43 years, 52.9% male) completed a baseline – administered by a trained researcher ‐ and three month follow up visit – administered by an automated phonebot. Tasks included a spontaneous speech assessment and cognitive battery (immediate and delayed recall, digit span and verbal fluency). Participants were randomized to receive their cognitive test results after the final or after each study visit. Participants completed acceptability questionnaires electronically after each study visit.

Result

Retention was high (98.5%), with few technical issues (n = 6.7%), there was good inter rater reliability, and test scores were similar when administered by phonebot compared to human administrator in most subtests. A significant lower mean score in digit span was noted at follow up. These findings indicate general feasibility of the assessment. Participants preferred a human tester but rated the automated assessments as acceptable and would be happy to complete a phonebot assessment again, confirming the ease of use of the technology and comfort of completing cognitive tasks on the phone. Participants generally reported feeling happy to receive their cognitive tests results, and this disclosure did not cause participants to feel worried.

Conclusion

The results from this usability and acceptability analysis suggests that completing this brief battery of cognitive tests via a telephone call is both acceptable and feasible in a midlife‐to‐older adult population in the UK, living at risk for AD.
Beta to Theta Power Ratio in Electroencephalogram Periodic Components to Discriminate Mild Cognitive Impairment and Alzheimer’s Dementia
Authors: Azami Hamed , Zrenner Christoph , Brooks Heather , Zomorrodi Reza , Blumberger Daniel M. , Fischer Corinne E. , Flint Alastair , Herrmann Nathan , Kumar Sanjeev , Lanctôt Krista L. , Mah Linda , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K.
Published: December 2023

Background

Alzheimer’s disease dementia (AD) and mild cognitive impairment (MCI) are often associated with abnormalities in full power spectrum of electroencephalogram (EEG), including the ratio of beta/theta. Full spectrum EEG consists of aperiodic and periodic components with the latter being better associated with cognition. We investigated whether the aperiodic and periodic power components of EEGs are disrupted differently in individuals with MCI vs. AD vs. healthy controls (HC), and whether a periodic based beta/theta ratio better differentiates the three groups than a ratio based on the full spectrum.

Method

Data were collected in 199 participants ‐ 44 with HC (mean (SD) age: 69.1 (5.3) years), 114 with MCI (72.3 (7.5)), and 41 with AD (75.6 (6.5)). We cleaned the data using a band‐pass filter with cut‐off frequencies 1 and 45 Hz and then independent component analysis. We then used the “fooof” toolbox to decompose the EEGs into their aperiodic and periodic components. We used the area under the receiver operating characteristic curve (AUCROC) of a logistic regression classifier to distinguish HC from MCI and AD participants, and MCI from AD participants, using beta/theta ratios based on the periodic power spectrum vs. full power spectrum.

Result

There was an increase in full spectrum powers for delta, theta, and gamma, and a decrease of relative power for beta in AD participants compared to HC and MCI participants. In contrast, there were no differences in aperiodic background EEG components among HC, MCI, and AD participants. Overall, the periodic and full spectrum comparisons among the three groups were comparable except for the periodic based analysis that showed a difference between MCI and HC in the occipital beta/theta ratio (Bonferroni corrected p = 0.036). Classifiers based on beta/theta power ratio in EEG periodic components distinguished AD from HC and MCI with high AUCROC values (0.94 and 0.83, respectively), and outperformed classifiers based on beta/theta power ratio in EEG all oscillations (0.078 and 0.67, respectively).

Conclusion

This study supports an advantage of a periodic based analysis over a full EEG spectrum analysis and the use of occipital beta/theta power ratio based on periodic components as a screening tool for AD.
NOTCH2NLC trinucleotide interruptions are associated with cognitive impairment in neuronal intranuclear inclusion disease (NIID)
Authors: Tan Yi Jayne , Xu Zheyu , Chen Zhi‐Yong , Lim Weng Khong , Ting Simon Kang Seng , Yu Wai Yung , Cheng Qian Hui , Foo Jia Nee , Tan Eng‐King , Lim Tchoyoson CC , Ng Adeline Su Lyn
Published: December 2023

Background

Abnormal GGC expansion within the NOTCH2HLC gene causes neuronal intranuclear inclusion disease (NIID), a rare neurodegenerative disease with variable clinical manifestations, including cognitive dysfunction. In addition to GGC repeats, there are two forms of repeated interruptions, GGA and AGC, within NOTCH2NLC repeats. Previous studies reported fewer GGA and more AGC interruptions in patients with Parkinson Disease; fewer GGA and AGC interruptions in patients with essential tremor, compared to NIID patients. These results suggest that trinucleotide interruptions within the NOTCH2NLC GGC repeats could influence the phenotype of disease, although the mechanism is not known.

Methods

We looked at the repeat compositions in NOTCH2NLC in NIID patients with and without cognitive impairment (CI). NOTCH2NLC repeats were screened by long‐read sequencing on the Oxford Nanopore platform.

Results

In 13 NIID patients with NOTCH2NLC repeat expansion, 9 (69%) presented with CI. Patients with CI were older [mean (SD) = 69.7 (5.8) vs 63.3 (7.2)], had later age at onset [63.2 (6.5) vs 59.8 (7.1)] and longer disease duration [6.9 (5.2) vs 3.5 (3.9)] than patients without CI. The NOTCH2NLC repeats range from 89‐138 repeats in patients with CI; 82‐166 repeats in patients without CI. Patients with CI carried more GGC repeats [97.7 (1.7) vs 92.8 (9.0)] and less GGA [0.8 (1.3) vs 2.2 (2.8)] and AGC [0.6 (1.0) vs 3.5 (7.4)] interruptions within NOTCH2NLC, compared to patients without CI.

Conclusion

Our results suggest that NIID patients with cognitive impairment have a purer GGC repeat in NOTCH2NLC compared to patients without cognitive impairment, supporting previous studies that repeat interruptions may modify clinical manifestation of NIID.
Cerebral amyloid angiopathy frequency at baseline and after 4 years of follow‐up in the INSIGHT‐preAD study
Authors: Blanc Clémence , Houot Marion , Villain Nicolas , Younsi Nadjia , Dubois Bruno , Alamowitch Sonia , Bombois Stéphanie
Published: December 2023

Background

Cerebral amyloid angiopathy (CAA) diagnostic is of special interest due to its association with cognitive impairment, Alzheimer disease (AD) and Amyloid‐Related Imaging Abnormalities (ARIA) in trials with anti‐amyloid immunotherapies. We aimed to assess the frequency of CAA diagnosis and associated lesions in subjects with cognitive complaint and normal cognition enrolled in the INSIGHT‐preAD study.

Method

Cognitively normal elderly with memory complaint included in the INSIGHT‐preAD study were assessed with multimodal explorations for 5 years follow‐up. 3T MRI‐scans were performed at baseline and during follow‐up at 2 and 4 years. Lobar cerebral microbleeds (CMB), cortical superficial siderosis (CSS), enlarged perivascular spaces (EPVS) and white matter hyperintensities (WMH) were rated according to validated scales and guidelines. Boston criteria V2.0 were applied to diagnose possible and probable CAA.

Result

Among the 318 subjects (median [Q1, Q3] age: 76.4 [74.1, 78.5] years, 201 (63.2%) women) enrolled at baseline, 41 (12.9%) had at least one lobar CMB, 4 (1.3%) CSS, 68 (21.7%) severe EPVS in the centrum semi‐ovale and 245 (77%) WMH with a spot pattern ≥10. The median FAZEKAS score was 2.0 [1.0, 2.0]. At baseline, 251 (78.9%) subjects had CAA: 218 (68.5%) possible CAA and 33 (10.4%) probable CAA with a median number of CMB of 1.0 [1.0, 1.0]. Compared to non‐CAA subjects (n = 67), those with probable CAA at baseline were not different on demographics and vascular risk factor, had more executive dysfunction, and tended to be associated with Apoe4 status and lower hippocampal volume. After 2‐ and 4‐ years of follow‐up, 81.2% and 81.3% of the subjects still in the study had CAA, with 13.3% and 14.1% of probable CAA respectively, and the number of subjects with CMB increased to 15.9% and 18.3%.

Conclusion

In the INSIGHT‐preAD study, the high frequence of CAA, with minimal change after 4 years follow‐up, was essentially due to the non‐hemorrhagic lesions. The hemorrhagic lesions (CMB and CSS) were uncommon, probably underestimated by the MRI T2* sequence. These results have implications in clinical setting and could be useful in pre‐symptomatic AD anti‐amyloid immunotherapy trial.
Formal and informal healthcare utilization in MCI and mild dementia due to AD: Cross‐sectional and longitudinal analyses of RUD‐Lite data from the Tauriel Study
Authors: Teng Edmond , Li Yihao , Blendstrup Mira , Lansdall Claire J
Published: December 2023

Background

The Resource Utilization in Dementia‐Lite (RUD‐Lite) scale measures both formal healthcare utilization and informal caregiver time required by individuals with cognitive impairment. The RUD‐Lite has been incorporated into multiple observational and interventional studies of participants with Alzheimer’s disease (AD) dementia of varying severity. However, RUD‐Lite data for earlier stages of AD such as mild cognitive impairment (MCI) is limited and is primarily from observational studies. As healthcare utilization may differ between participants in observational versus interventional studies, we analyzed data from the Tauriel study of semorinemab in MCI and mild dementia due to AD (NCT03289143).

Methods

We performed cross‐sectional and longitudinal RUD‐Lite comparisons between MCI (n = 160) and mild dementia (n = 288) cohorts of the Tauriel study, exploring formal healthcare usage (hospital admissions, emergency department visits, outpatient visits, and ancillary services) and informal caregiver time for assistance with basic (BADLs) and instrumental (IADLs) activities of daily living and participant supervision. Both unadjusted and adjusted (for baseline usage, age, sex) analyses were performed on longitudinal data.

Results

Baseline cross‐sectional analyses (Table 1) indicated that mild dementia participants required significantly greater caregiver time for assistance with IADLs than MCI participants. Other formal and informal healthcare utilization indices did not differ between groups. Unadjusted longitudinal analyses across 18 months (Figure 1) revealed significant increases in informal caregiver assistance with BADLs (MCI:+40%, mild dementia:+231%), IADLs (MCI:+31%, mild dementia:+34%), and supervision (mild dementia:+219%) and in ancillary service usage (mild dementia:+345%). Adjusted longitudinal analyses (Figure 2) revealed significantly greater increases in mild dementia versus MCI for assistance time with BADLs, IADLs, and supervision.

Conclusion

Informal caregiver time spent providing assistance in early AD increases with disease severity and longitudinal changes are detectable in MCI over 18 months. Formal healthcare utilization indices were less sensitive to disease progression. While the RUD‐Lite results from this interventional study are consistent with observational data from analogous populations, less caregiver assistance time was reported in our cohort. When using RUD‐Lite outcomes in future early AD studies, investigators may need to account for their participant population (e.g., observational versus interventional) in their study design.
AZP2006, a New Promising Treatment for Progressive Supranuclear Palsy patients. Phase 2a Study Assessing Tolerability, Safety and Pharmacokinetics. Effect on Biomarkers and Clinical Readouts
Authors: Verwaerde Philippe , Estrella Cecilia , Blondel Aurélien , Signore Susanna Del , Callizot Noelle
Published: December 2023

Background

Progressive Supranuclear Palsy (PSP) is a rare progressive, fatal neurodegenerative 4‐repeat tauopathy. AZP2006 (INN: Ezeprogind) is a first‐in‐class disease‐modifying oral small molecule acting via its strong binding to the complex Progranulin (PGRN) / Prosaposin (PSAP), able to increase the circulating contents of PGRN (plasma and brain) in non‐clinical models. Preclinically, AZP2006 promotes neuron survival, synaptic function, decreases Tau hyperphosphorylation and reduces neuroinflammation (in vitro and in vivo models of Alzheimer’s disease, PSP and Parkinson’s disease). In healthy volunteers Phase 1 studies, AZP2006 was well tolerated with a good safety profile.

Method

AZP2006 safety, tolerability and pharmacokinetic profiles in plasma, whole blood, and CSF were investigated in a randomized, double‐blind, placebo‐controlled, parallel group study comparing 2 doses of AZP2006 (60 mg once daily during the 12‐week treatment period and 80 mg once daily for 10 days followed by 50 mg once daily) with placebo in 36 men and women aged ≥40 years and ≤80 years diagnosed with probable or possible PSP. Patients were observed for an additional 12‐week follow‐up period (NCT04008355).

In secondary objectives, CSF biomarkers including PGRN for the target engagement and markers of neurodegeneration (NfL, phospho‐tau T181) as well as markers of neuroinflammation (sTREM2, interleukins, etc.) were quantified. In addition, exploratory efficacy objectives evaluating clinical endpoints (PSP‐RS total, PSP Gait, PSP Ocular, CGI‐ds, Schwab and England ADL) were investigated.

Result

AZP2006 was safe and well tolerated; no related SAEs were reported. PK profile confirmed the long AZP2006 half‐life (as predicted in a prior popPK model). High brain penetrance was observed and AZP2006 CSF expected levels were achieved. In addition, the target engagement was confirmed by significant increase (vs baseline) of PGRN plasma levels. A PD‐PK analysis is planned.

Conclusion

AZP2006 treatment showed promising effects after a 3‐month‐treatment. Considering these promising results, an open‐labelled extension (OLE) was started (60 mg daily) in France. In addition, a larger Phase 2b/3 study in PSP patients testing AZP2006 efficacy over 12‐month‐treatment is under preparation.
Subgroups of Alzheimer’s Disease determined by longitudinal change across three domains of cognition
Authors: Scollard Phoebe , Mukherjee Shubhabrata , Choi Seo‐Eun , Lee Michael L. , Klinedinst Brandon S , Gibbons Laura E , Trittschuh Emily H. , Mez Jesse B. , Saykin Andrew J. , James Bryan D , Crane Paul K
Published: December 2023

Background

There is evidence that Alzheimer’s Disease (AD) may have distinct subtypes. Most approaches for identifying subgroups use cross‐sectional data. Here we use longitudinal cognitive test data from two large cohort studies to determine if there are distinct patterns of cognitive decline among those with AD and if those patterns differ across three domains of cognition.

Method

We used data from the Rush Memory and Aging Project and Religious Orders Study (Table 1). Previously, cognitive test items were assigned to a single domain of memory, language, or executive function and scores for each domain were estimated using confirmatory factor analysis. We used Growth Mixture Models to estimate trajectories of decline starting at AD diagnosis and identified subgroups with differing trajectories. Each domain was modeled individually and in a combined model that included distinct latent processes for each domain. Models with one to five classes were estimated and the number of classes was selected using Bayesian Information Criterion (BIC) and entropy.

Result

The two class models fit best for each of the individual domains (Figure 1). For memory and language one class was characterized by a higher intercept and steeper slope while the other had a lower intercept and flatter slope. For executive function the two classes had similar intercepts, but different slopes. Five classes best fit the data in the combined model. The pattern of decline within a class was similar across the three domains (Figure 2). For each domain, four of the classes were differentiated from each other by lower intercepts and increasingly steep slopes, while a fifth class had the lowest intercept, but a flatter trajectory over time.

Conclusion

We did not see different patterns across domains of cognition; knowing the trajectory of one cognitive domain explains the most likely trajectory of the other domains. Still, differences identified in patterns of overall decline may be important for AD treatment. Future work will focus on determining biological relevance of subgroups through association with genetic and other biomarkers as well as addressing methodological issues such as incorporating survival time and accounting for the presence of prevalent cases and floor scores.