bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive Assessment for Tagalog Speakers (CATS): A pilot study
Authors: Deleon Jessica
Published: December 2023

Background

As the US population of Asian Americans and Pacific Islanders (AAPI) over the age of 65 increases, the incidence of Alzheimer’s disease and related disorders (ADRD) in this group is expected to triple between 2008 and 2030. This group includes over 4 million Filipino Americans, who comprise the largest AAPI population in California and 10 other states. Although there is scarce literature detailing the prevalence of dementia among AAPI subgroups, one study found that Filipino Americans had the highest incidence rate of dementia (Mayeda et al., 2017). Despite the expected increase in the number of Filipino Americans with ADRD, no studies to‐date have validated neuropsychological measures in the United States for speakers of Tagalog (Filipino), one of the major languages spoken by Filipino Americans and the 4th most widely spoken language in the US. A major barrier to dementia care and diagnosis is the lack of linguistically and socioculturally appropriate cognitive tasks for Tagalog speakers. To address this need, we developed and piloted the Cognitive Assessment for Tagalog Speakers (CATS), the first neuropsychological battery for the detection of ADRD in Filipino American Tagalog speakers.

Method

We translated, adapted, and constructed de novo to measure performance across four main cognitive domains: visual/verbal memory, visuospatial functioning, speech and language, and frontal/executive functioning. Tasks were developed with a team of bilingual English/Tagalog and bicultural Filipino American/Canadian experts, including a neurologist, speech‐language pathologist, linguist, and neuropsychologist.

Result

To‐date, the CATS battery has been administered to 15 healthy control participants (age 61.8 ± 5.4 yrs, 5M/10F) at the University of California, San Francisco. These preliminary results show the feasibility of the measures but also demonstrated the need to consider effects of bilingualism, language typology, and cultural factors in the interpretation of results.

Conclusion

This project will lay the groundwork for norming and validation studies and will help solidify connections to a population that has been underrepresented in ADRD research. As we move towards treatment and cure of ADRD, linguistically and culturally appropriate cognitive tests become even more important for equitable care.
Delirium diagnostic 2012 to 2021, contribution of CAM and clinical nurses of the geriatric consultation team in CIUSSS de l’Estrie‐CHUS
Authors: Lacombe Guy , Bel‐Maréchal Maria , Cowan Cathy Mc , Sabourin‐Tremblay Émilie , Poulin Véronique
Published: December 2023

Background

To evaluate the evolution of diagnostic of delirium following the introduction of CAM as a geriatric vital sign as part of The Specialized Approach to Senior Care (l’approche adaptée à la personne âgée, AAPA) in University Hospital CIUSSS de l’Estrie‐CHUS in 2014.

Method

Training on CAM and delirium was given in 2014. The nurses of the geriatric consultation team make recommendations/coaching to the treating teams during geriatric consultations. We analyze ICD‐10 data from > 65‐year‐olds hospitalized at the CHUS before (2012) and after (2016). A criteria base analysis of the files with diagnosis of delirium on the discharge letter or a geriatric consultation of November 2016 describes the considerations related to delirium.

Result

Of the 32,000 hospitalizations at CHUS in 2016, 13,000 are over 65 years old and 1296 have a geriatric consultation. 2.2% in 2012 to 2.7% in 2016 had delirium according to the exit letter. That is 3% of 65‐75 year olds and 8% of those over 75. 102 consecutive files of geriatric nursing consultations from November 2016 are reviewed. 63 new diagnoses of delirium with an average of 3 recommendations from the AAPA to the treatment team.

Conclusion

Delirium remains under‐documented at release and improves little from 2012 to 2021. The modalities of use of the current tools remain insensitive. The support of geriatric consultation teams remains necessary to support the development of AAPA against delirium.
Self‐appraisal of cognitive performance in repeated daily digital assessments with amyloid and tau‐PET
Authors: Soberanes Daniel , Hsieh Stephanie , Molinare Cassidy , Weizenbaum Emma L , Jutten Roos J. , Vannini Patrizia , Dubbelman Mark A. , Gagliardi Geoffroy Pierre , Johnson Keith A. , Rentz Dorene M. , Sperling Reisa A. , Papp Kathryn V. , Amariglio Rebecca E.
Published: December 2023

Background

Lower self‐ratings of performance on single timepoint neuropsychological measures have been previously associated with elevated AD biomarkers, aligned with the notion of a period of heightened awareness of cognitive decline in preclinical AD. With the rise of digital tools, cognitive assessments can now be collected over multiple days to examine learning over repeated exposures, thought to be diminished in preclinical AD. However, it is unknown whether daily self‐appraisal of performance would mimic reduced learning observed in individuals with elevated biomarkers. In this study, we used the Boston Remote Assessment for Neurocognitive Health (BRANCH) platform to capture multi‐day learning curves and to analyze whether self‐evaluation of performance was associated with amyloid and tau PET in a sample of cognitively unimpaired older individuals.

Method

Our sample consisted of 193 cognitively unimpaired individuals (mean age = 74.1, 64.8% female, 85.5% Caucasian) already enrolled in a longitudinal observational study who underwent PiB‐ and Flortaucipir‐PET. Using the BRANCH platform remotely, participants completed two paired associative learning tests with repeated stimuli on their own digital devices for 7 consecutive days. A self‐evaluation was prompted at the end of each assessment, asking participants to rate their performance from 0‐100. Multi‐day learning curve metrics for objective performance (obj‐MDLC) and self‐appraisal (subj‐MDLC) were calculated for each participant. We examined correlations between obj‐MDLC and subj‐MDLC and using linear mixed‐effects models investigated the relationship between MDLCs, global β‐amyloid (Aβ) and tau burden in entorhinal (ET) cortex.

Result

Obj‐MDLC was moderately correlated with the subj‐MDLC (r = 0.61, p < 0.001) and showed that, on average, participants under‐estimated their performance on the tasks. Both higher Aβ and higher ET tau were associated with a decreased obj‐MDLC (Day*Aβ = ‐0.08, p = 0.015; Day*ET = ‐0.06, p = 0.020) and subj‐MDLC (Day*Aβ = ‐0.09, p = 0.021; Day*ET = ‐0.09, p = 0.003).

Conclusion

Participant’s self‐appraisal of their performance on the BRANCH tasks across days showed significant associations with tau and amyloid that were consistent with those seen with actual performance on the BRANCH tasks. These findings demonstrate that utilizing daily self‐appraisals, in addition to objective assessment, provides complementary information in early preclinical AD.
Associations Between Trauma, Cognition, and Depression in U.S. Older Adults: Findings from the Health and Retirement Study
Authors: Dong Fanghong , Britt Katherine Carroll , Hodgson Nancy A
Published: December 2023

Background

Despite the well‐known deleterious health effects of childhood and adulthood trauma and the aging of the global population, little is known about trauma experiences in older adults. Moreover, childhood trauma may beget adulthood trauma and alter life‐course trajectories of trauma exposure, and thus exhibit certain patterns in older adults. Using a national sample, this study aimed to (1) determine patterns of childhood and adulthood trauma, (2) examine their association with cognition and depression, and (3) investigate whether the association between trauma and depression is moderated by cognition.

Method

Data were from participants aged 60+ in the Health and Retirement Study in 2008 and 2012. Latent class analysis (LCA) was conducted to identify childhood and adulthood trauma patterns in 2008 (N = 6545). Depressive symptoms were measured by Center for Epidemiological Studies–Depression scale (CESD) and cognition was assessed by total cognition summary score (range 0‐35 and cognitive impairment defined as 8 or less) in both 2008 and 2012. The final sample size is 4684. Multiple regressions were conducted to examine cross‐sectional and longitudinal associations between trauma patterns, cognition, and depression, while moderation analyses were conducted to examine the moderating role of cognition, adjusting for age, gender, race, education, marital status, and body mass index.

Result

Participants had a mean age of 71.5(7.53) years, 58.4% female, and 85.7% White. A 3‐class LCA model was determined to be the best fit for the data with three patterns: (1) low trauma exposure (61.04%), (2) family life‐threatening events (20.07%) and (3) moderate trauma exposure (i.e., moderate probability of having experienced every type of trauma) (18.89%). Older adults experiencing family life‐threatening events or moderate trauma exposure have significantly worse cognition and higher depression. Furthermore, cognition moderated the association between trauma exposure and depression, especially for older adults who experienced family life‐threatening events.

Conclusion

Findings indicated significant associations between three distinct trauma patterns and depression, and the buffering role of cognition. Educating health professionals about trauma patterns, rather than only considering accumulation, could optimize targeted, integrated public health and clinical strategies to improve cognitive performance and decrease depression in vulnerable older adults who have experienced trauma.
Multi‐omic characterization of a novel FTD/ALS‐associated variant in ANXA11
Authors: Snyder Allison , Ryan Veronica , Qi Andy , Johnson Kory , Reed Xylena , Cookson Mark R , Ward Michael
Published: December 2023

Background

Mutations in Annexin A11 (ANXA11) disrupt its normal function and cause FTD/ALS spectrum disorders. Pathophysiologically, disease‐associated ANXA11 mutations alter its phase separation properties, resulting in ANXA11 aggregation, alterations in lysosomal‐RNA granule co‐trafficking, and TDP‐43 mislocalization. Multiple mutations in ANXA11 have been linked to FTD and ALS, but as genetic testing has become more accessible and affordable, additional variants of uncertain significance in in this and other genes have been identified. Determining whether these variants play causal roles in disease is a major challenge in the field.

Method

We identified a novel variant in ANXA11 (P93S) in a kindred that segregates with an FTD‐spectrum disorder with unusual radiographic features. We developed a pipeline to model ANXA11 variants in iPSC‐derived microglia and neurons, which scRNAseq analysis of human cortex revealed as the highest ANXA11 expressing cell types. Following differentiation, we characterized the proteomic, transcriptomic, and microscopy signature of the P93S variant compared to known pathogenic mutations in ANXA11.

Result

Mutant P93S ANXA11 expression in iPSC‐derived neurons resulted in increased ANXA11 fibrils and loss of nuclear TDP‐43. Proteomic analysis revealed disruption of multiple cellular pathways associated with neurodegenerative diseases.

Conclusion

Our iPSC neuron models of this variant recapitulate several hallmark pathological features of mutations in ANXA11 indicating that this novel ANXA11 P93S variant is likely pathogenic. Omic signatures of this variant provide additional evidence of pathogenicity. Importantly, the pipeline that we developed provides a proof‐of‐concept for future evaluation and adjudication of additional variants of uncertain significance across FTD/ALS associated genes.
Palmitoyl transferase zDHHCs: novel targets in Alzheimer’s disease
Authors: Fusco Salvatore , Natale Francesca , Spinelli Matteo , Gulisano Walter , Rinaudo Marco , Puzzo Daniela , Grassi Claudio
Published: December 2023

Background

Growing evidence points to altered metabolic signals as a risk factor for Alzheimer’s disease (AD). The high fatty acid levels and brain insulin resistance (BIR) found in AD brains may impinge on protein S‐palmitoylation, which is a post‐translational modification critically involved in the regulation of neuronal protein localization and synaptic function. Our previous findings highlighted the critical role of aberrant palmitoylation in BIR‐dependent memory impairment (Spinelli et al., 2017).

Method

We analyzed both the expression of palmitoyl‐transferase enzymes (zDHHCs) in mouse AD brains and S‐palmitoylation levels of key proteins in human AD brains. We also tested the effect of chronic intranasal injection of the palmitoylation inhibitor 2‐bromopalmitate (2BP) on a large cohort of male and female 3xTg‐AD mice, starting from 3 months of age, by performing cognitive (novel object recognition and object displacement tests), electrophysiological (LTP), immunohistochemical (Abeta deposition) and molecular analyses (Abeta measurement by ELISA). Finally, we investigated the effects of lentiviral particles‐mediated zDHHC7 or zDHHC21 silencing in the hippocampus of 3xTg‐AD.

Result

We found increased levels of zDHHC7 and zDHHC21 in the hippocampus of 3xTg‐AD mice and aberrant palmitoylation of key enzymes triggering beta amyloid aggregation in human AD brains. 2BP delayed the onset of memory deficits in both male and female 3xTg‐AD mice. More importantly, 2BP significantly enhanced cognitive performances in 6‐, 9‐ and 12‐month‐old animals. Accordingly, electrophysiological analyses on hippocampal brain slices from 2BP‐treated 3xTg‐AD mice revealed greater long‐term potentiation at CA3‐CA1 synapses. In addition, both 2BP‐treated male and female mice showed lower Abeta deposition in hippocampus and a significant extension of lifespan. Finally, genetic inhibition of palmitoyl transferase zDHHC7 reverted the aberrant palmitoylation of proteins involved in synaptic plasticity and APP metabolism, and counteracted the onset of neurodegeneration and cognitive deficits in 3xTg‐AD mice.

Conclusion

This is the first preclinical study on the effect of 2BP treatment on AD‐related cognitive decline. Our data indicate that aberrant palmitoylation plays a critical role in the onset and progression of AD and unveil the potential druggable role of zDHHC enzymes in dementia‐related neurodegenerative disorders.
Applying CVR, composite value ratio, to brain MRI volume and thickness as an atrophy biomarker for Alzheimer’s disease clinical trials
Authors: Saguer Isaac Llorente , Oxtoby Neil P
Published: December 2023

Background

Biomarkers are key tools for clinical trials of putative therapeutics in Alzheimer’s Disease. Biomarkers with higher signal‐to‐noise ratio can improve the efficiency of drug development through reduced sample sizes and shorter trial durations. Image‐based biomarkers such as SUVR from PET and volumes from MRI have been used as secondary outcomes in many studies. Previously, we showed how our biomarker‐discovery algorithm CVR (combined value ratio) outperformed tau‐PET SUVR in clinical trial applications [Saguer et al., Alzheimer’s ∖& Dementia 2022]. Here, we apply the same methodology to brain volumes and cortical thickness, which are both cheaper than PET and routinely collected.

Methods

Data: We analyse longitudinal MRI data in ADNI from 1622 participants: 556 cognitively unimpaired (CU) and 1066 cognitive impaired (CI), keeping the latest three visits for CU, and earliest for CI, to better target the transition from CU to CI.

Model: A genetic algorithm explores combinations of 68 regions (averaged) defined by the Desikan‐Killiany atlas in FreeSurfer, separately for volume (including ventricles) and cortical thickness (all log‐transformed). We define CVR as the ratio of two data‐driven composite regions.

Evaluation: A linear mixed‐effects model estimates 1) group separation in atrophy (t‐statistic, CU vs CI fixed effect) and 2) longitudinal precision (std of model residuals). We calculate 3) sample size estimates (SSE) for a hypothetical 12 months‐long clinical trial involving CI individuals designed for 80% power, with 20% treatment effect. Metrics 1 and 3 drive the biomarker discovery algorithm.

Results

Table‐1 shows our CVR metrics wrt traditional biomarkers from the literature (whole‐brain and hippocampus volume, average cortical thickness of all regions and a subset). CVR improved group separation by 1.7x, longitudinal precision by 1.7x and reduced sample size by 5.1x.

Discussion

The data‐driven biomarker from volumetric measures is the ratio of two composites (Figure‐1): one is highly linked to neurodegeneration, while the other takes advantage of more stable or growing regions, like the ventricles. Having these opposite characteristics in a ratio boosts its performance.

Conclusion

Our algorithm discovered a ratio‐based imaging biomarker that could vastly improve clinical trials in Alzheimer’s disease using routinely collected MRI.
Microglial deletion of C1q rescues AD cognitive decline and synaptic loss
Authors: Petrisko Tiffany J , Gomez‐Arboledas Angela , Chu Shu‐Hui , Tenner Andrea J
Published: December 2023

Background

The complement (C’) system contributes to enhanced inflammation and cognitive decline in Alzheimer’s disease (AD). Previous studies have demonstrated constitutive deletion of the classical initiator protein, C1q, reduces pathology and synaptic loss in AD mouse model. As it is now known that microglia are the primary producers of C1q in the brain, the main objective of this study was to determine if microglial specific deletion of C1q would rescue cognitive impairment and synaptic loss in AD.

Method

C1qaFLlFL:CX3CR1Cre (designated C1qΔMG)mice, which experience tamoxifen‐independent deletion of microglial C1q by 2 months of age, were crossed to Arctic: C1qaFl/Fl: mice to generate WT and Artic mice with and without the CX3CR1Cre transgene. At 10 months of age, mice underwent behavioral testing of hippocampal dependent spatial memory, including object location memory (OLM) and spatial reference Y‐maze. Tissue was collected at the end of testing and immunostained for pre (VGlut1) and post (PSD95) synaptic makers and Z‐stacks using superresolution microscopy in the CA1 of the hippocampus were obtained. The density of pre‐ and post‐synaptic puncta and their colocalization was assessed using IMARIS.

Result

While both male and female Arctic mice displayed a significant impairment in long‐term memory, as assessed by OLM, microglial deletion of C1q rescued cognitive deficits in male but not female Arctic mice. Male Arctic C1qΔMGmice also performed better on Y‐maze testing than Arctic controls. Similar sex‐dependent results were observed in synaptic density. Female Arctic C1qΔMG mice displayed reduced levels of PSD95 and Vglut1 puncta compared to female Arctic mice, as well as a trending reduction in colocalization. In contrast, male Arctic C1qΔMG mice displayed increased levels of PSD95, trending reductions in VGlut1 compared to male Arctic controls, and trending increases in synaptic colocalization, suggesting an increase in functional synapses in the male mouse.

Conclusion

Deletion of C1q in microglia prior to amyloid plaque deposition protects against cognitive decline and synaptic loss in a greater extent in males than females.
Extracellular Tau Oligomers Damage the Axon Initial Segment by an Endogenous Tau‐Dependent Mechanism
Authors: Best Merci N , Lim Yunu , Ferenc Nina , Kim Nayoung , Wang Dora Bigler , Sharifi Kamyar , Wasserman Anna , McTavish Sloane , Siller Karsten , Jones Marieke K , Jenkins Paul M , Mandell James W , Bloom George S
Published: December 2023

Background

Neuronal polarity and synaptic connectivity are compromised in Alzheimer’s disease (AD) and other tauopathies. The axon initial segment (AIS) is a key structure for regulating polarity and functions of neurons. It occupies the first 20‐60 µm of the axon, comprises a diffusion barrier that segregates axon‐enriched from somatodendritic‐enriched molecules, and has a high concentration of voltage‐gated ion channels that generate action potentials. Extracellular amyloid‐β oligomers compromise AIS integrity. However, effects on the AIS of toxic tau species, including extracellular oligomers (xcTauOs) that spread tau pathology from neuron to neuron by a prion‐like process, whereas unknown. Therefore, we wanted to test the hypothesis that AIS structure is sensitive to xcTauOs.

Method

Primary cortical neurons derived from either wild type (WT), or tau knockout (KO) mice were exposed to xcTauOs or vehicle. Quantitative western blotting and immunofluorescence microscopy with an antibody against the AIS‐enriched protein TRIM46 was used to monitor effects on the AIS. The same methods were also used to compare TRIM46 and two other AIS proteins, ankyrin‐G and neurofascin‐186 in human hippocampal tissue obtained from AD and age‐matched non‐AD donors.

Result

In cultured WT, but not TKO neurons, xcTauOs cause a trend toward AIS shortening and reduce the concentration of the resident AIS protein, TRIM46, without affecting total TRIM46 levels. Lentiviral‐driven human tau expression in tau KO neurons rescues TRIM46 sensitivity to xcTauOs. In human AD hippocampus, AIS length and TRIM46 concentration within the AIS are reduced in neurons containing neurofibrillary tangles (NFTs), without affecting the overall protein levels of multiple resident AIS proteins.

Conclusion

These collective findings demonstrate that in cultured neurons, xcTauOs cause partial AIS damage by a mechanism dependent on intracellular tau, thereby raising the possibility that AIS reduction in AD is caused by xcTauOs working in concert with endogenous neuronal tau.
Validation of the European Cross‐Cultural Neuropsychological Test Battery (CNTB) for the assessment of mild cognitive impairment due to Alzheimer’s disease and Parkinson’s disease in Spain
Authors: Delgado‐Álvarez Alfonso , Nielsen T Rune , Delgado‐Alonso Cristina , Valles‐Salgado María , López‐Carbonero Juan Ignacio , García‐Ramos Rocío , Gil‐Moreno María José , Díez‐Cirarda María , Matias‐Guiu Jorge , Matias‐Guiu Jordi
Published: December 2023

Background

The Cross‐Cultural Neuropsychological Test Battery (CNTB) is a novel comprehensive neuropsychological battery developed from a multicultural approach. We aimed to validate the CNTB in patients from the majority population with Alzheimer’s disease (AD), including mild cognitive impairment (MCI) and mild dementia stages, and Parkinson’s disease with MCI (PD‐MCI).

Methods

Thirty patients with AD‐MCI, 30 with AD‐dementia (AD‐D), and 30 with PD‐MCI were enrolled. Each clinical group had a specific healthy control group (HC) with no differences in sex, age, or years of education. We performed intergroup comparisons, ROC analysis, and calculated the corresponding cut‐off points based on Youden’s index.

Results

AD‐MCI showed lower scores than HC in those subtests associated with episodic memory and verbal fluency, while AD‐D also scored lower in executive function and visuospatial tests with large effect sizes. Participants with PD‐MCI showed lower performance in memory and executive function, particularly on error scores, with large effect sizes, compared with HC. While AD‐MCI showed lower memory scores, PD‐MCI had a lower performance in executive functions, comparing both groups. We found evidence of convergent validity with standardized neuropsychological tests measuring the same cognitive domains. Cut‐off scores were similar to previous studies conducted in other cultures.

Conclusions

The CNTB showed appropriate diagnostic properties and convergent validity in AD and PD, including the early stages of the disease. This supports the utility of the CNTB for the early detection of cognitive impairment in AD and PD.
The effect of study partner characteristics on the reporting of neuropsychiatric symptoms in older adults with and without dementia
Authors: Guan Dylan X. , Mudalige Dinithi M , Munro Catherine E , Nosheny Rachel L , Smith Eric E. , Ismail Zahinoor
Published: December 2023

Background

Valid assessments of neuropsychiatric symptoms (NPS) are key in older adults with or without dementia, often relying on study partner (SP) report. NPS are linked to poorer health outcomes, denoting higher risk for incident cognitive decline and dementia, especially when these NPS emerge in later life and persist (i.e., mild behavioral impairment; MBI). We investigated the effect of study partner (SP) characteristics on SP‐reported NPS in older adults with and without dementia (normal cognition or mild cognitive impairment), and compared MBI‐associated rates of incident dementia across different SP characteristics.

Method

Cross‐sectional (n = 26825) and longitudinal (n = 2526) analyses were conducted on participant‐SP dyads in the National Alzheimer’s Coordinating Center Uniform Data Set. NPS were measured using the SP‐rated Neuropsychiatric Inventory Questionnaire (NPI‐Q). MBI status in dementia‐free participants was defined by the presence of NPS across two consecutive visits. SP characteristics of interest were age, sex, and relationship to participant (spouse, child, other). Multivariable logistic regressions, adjusted for participant age, sex, education, and dementia status were used to model participant NPS presence/absence as a function of SP characteristics. Cox proportional hazards regression was used to compare the hazard of incident dementia in MBI participants across different SPs.

Result

Participant and SP characteristics are summarized in Table 1. Across the entire cohort, SPs who were younger, female, or a spouse or child of the participant were more likely to report participant NPS [Table 2]. Furthermore, in dementia‐free participants, female‐spouse SPs reported participant MBI with greater odds than male spouses, but non‐spouse SPs reported participant MBI similarly to one another with lower odds regardless of sex [Figure 1]. This interaction was not observed for NPS in dementia, which were highly prevalent regardless of SP sex and relationship to participant. Finally, participants with MBI reported by SPs who were spouses or children progressed to dementia at a greater rate than other SPs.

Conclusion

SP characteristics including age, sex, and relationship to participant are linked to greater endorsement of NPS in older participants with and without dementia. In scenarios where accurate assessments of NPS are required, SPs characteristics could be considered in recruitment and analysis.
Acarbose ameliorates western diet‐induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer’s disease
Authors: Sonsalla Michelle M , Babygirija Reji , Johnson Madeline , Cai Samuel , Yeh Yang , Calubag Mariah , Trautman Michaela , Lamming Dudley
Published: December 2023

Background

Many age‐related diseases are major risk factors of Alzheimer’s disease (AD), such as type II diabetes mellitus and cardiovascular disease. As such, there is a growing body of interest in determining if already in use geroprotective interventions for these disorders may also be beneficial in AD. One such intervention is acarbose, an anti‐diabetic drug that improves glucose homeostasis, reduces risk of myocardial infarction, and extends lifespan in various mouse models.

Method

We administered either a western diet or a western diet containing acarbose to diet‐induced obese male and female 3xTg mice starting at 6 months of age. Over the following 6 months, we examined a number of facets of metabolic health and analyzed cognitive function using Barnes maze. After sacrificing mice at 12 months of age, we analyzed aspects of AD pathology in the brain using Western blotting and immunohistochemistry.

Result

Both male and female 3xTg mice treated with acarbose exhibited decreased body weight and adiposity despite increased food consumption. Acarbose‐treated mice also had an overall improvement in glycemic control and increased energy expenditure. Female mice showed dramatic improvements in cognition and AD pathology, and males exhibited minor improvements as well. Preliminary data also suggest that there is increased gliosis in mice fed a western diet, which may be ameliorated by acarbose.

Conclusion

In the context of a western diet, acarbose has dramatic benefits on metabolic health, cognitive health, and AD pathology. This suggests that there is potential for already in use geroprotective pharmaceuticals such as acarbose to ameliorate AD pathology.
Exploring the multimeric tau interactome and its convergence with human tauopathy
Authors: Shapley Sarah M , Bagchi Pritha , Bowen Christine A , Dammer Eric B. , Rangaraju Srikant , Seyfried Nicholas T
Published: December 2023

Background

Neurofibrillary tangles (NFTs) comprised of the phosphorylated Tau protein are a core pathological feature of Alzheimer’s disease (AD) and several other neurodegenerative diseases collectively termed tauopathies include progressive supranuclear palsy, corticobasal degeneration, and subtypes of frontotemporal dementia. Physiological Tau is involved in many processes essential for cell function via protein‐protein interactions. However, under pathological conditions, the gain or loss of Tau protein interactions is an important consequence of disease pathophysiology and may result in the ‘rewiring’ of Tau protein‐protein interaction (PPI) networks. Therefore, modeling and identifying Tau interacting partners could reveal signaling mechanisms and therapeutic targets in tauopathies.

Method

To gain an unbiased understanding of the aggregated Tau interactors, we generated a split Turbo Tau (sTurbo Tau) proximity labeling system. We chose to express the isolated Tau repeat domain (RD) containing a pro‐aggregation P301L familial tauopathy substitution. Immunocytochemistry (ICC) and Western blot (WB) were performed in sTurbo Tau expressing cells following biotin labeling. Biotinylated proteins were affinity purified and analyzed in triplicate via mass spectrometry (MS) to identify these Tau interacting partners. Differential expression and Gene Ontology (GO) analyses were performed. We overlapped the sTurbo Tau interactors in cell culture and Tau interacting partners in AD brain lysates to further validate our model.

Result

ICC displayed speckle‐like Tau‐positive aggregates in the cytoplasm and nucleus that colocalized with biotin. WB with streptavidin dye also revealed high and low molecular weight biotinylated proteins in sTurbo Tau cells. MS identified nearly 1,900 proteins enriched in sTurbo Tau lysates compared to controls. GO analysis of these putative Tau interacting proteins confirmed various pathways, including cellular structural components, RNA binding, and translation. This overlap revealed 176 shared partners with roles in translation, synaptic processing, RNA‐binding, and proteasome function. Candidate spliceosome proteins, U1‐70K, U1A, and SNRPD2, have previously been shown to aggregate and colocalize with Tau in AD. Additionally, HSP90 family members were enriched in the overlapped datasets and are the target of mechanistic studies.

Conclusion

Collectively, we established a cell‐based Tau proximity labeling approach to identify Tau co‐aggregation partners relevant to human AD. This provides insight into novel pathways and therapeutic targets in disease.
Sex prevalence in mild behavioral impairment: a systematic review and meta‐analysis
Authors: Mudalige Dinithi M , Goodarzi Zahra , Ebrahim Inaara , Guan Dylan X. , Ismail Zahinoor
Published: December 2023

Background

Mild behavioral impairment (MBI) leverages the risk associated with later‐life emergent and persistent neuropsychiatric symptoms (NPS) to identify a high‐risk group for incident cognitive decline and dementia. While sex differences in NPS prevalence have been reported in Alzheimer’s dementia, these differences have not been well explored in dementia‐free samples. Here, we investigated sex differences in MBI prevalence across normal cognition (NC) and mild cognitive impairment (MCI). We also included rater in the analyses (i.e., self, informant, clinician), given that dementia‐free older adults may self‐report symptoms or attend clinic without an informant.

Methods

EMBASE, MEDLINE, PsycINFO, and grey literature were systematically searched for articles mentioning MBI. Retrieved abstracts and full‐text articles were screened by two independent reviewers and included if sex‐specific MBI prevalence was reported. A standardized data extraction sheet was used for demographics, cognitive diagnosis, rater, and MBI prevalence within each sex. A risk of bias assessment was conducted. A random‐effects meta‐analysis calculated the pooled prevalence of MBI in each sex, stratified by cognitive diagnosis (NC, MCI, and combined NC/MCI samples) and symptom rater.

Result

A total of 5783 articles (EMBASE n = 2752, MEDLINE n = 1798, PsycINFO n = 1233) were retrieved from the search; 165 full‐texts were screened, and 64 were included for data extraction (Figure 1). In females, MBI prevalence increased as cognitive status declined from NC (25%) to mixed cognition (32%) to MCI (43%) [Table 1]. MBI prevalence was highest when reported by informants (35%), followed by clinicians (23%), and self‐reports (20%) [Table 2]. Similarly, in males, MBI prevalence increased with declining cognition (NC = 27%, NC/MCI = 37%, MCI = 48%). MBI prevalence was highest when reported by informants (40%), followed by self‐reports (23%) and clinicians (22%).

Conclusion

In both males and females, approximately a quarter of NC and nearly half of MCI participants had symptoms of MBI; prevalence was slightly greater in males. Informants reported MBI symptoms more than clinicians or participants themselves. These findings suggest that MBI is prevalent in dementia‐free older adults of both sexes and that informants are essential given the increasing MBI prevalence with declining cognition.
Mediation Analysis Identifies Amyloid Imaging Genetic Patterns for Cognitive Outcomes in Alzheimer’s Disease
Authors: Lee Brian N , Bao Jingxuan , Tong Boning , Risacher Shannon L , Saykin Andrew J. , Moore Jason H , Kim Dokyoon , Davatzikos Christos , Long Qi , Ritchie Marylyn D. , Shen Li
Published: December 2023

Background

Previous genetic studies of Alzheimer’s Disease (AD) utilized features derived from florbetapir (AV45) PET imaging (Lee et al., BMC Genomics 85(2022)). Genetic analysis of florbetaben (FBB) PET FreeSurfer‐defined ROI‐specific SUVrs provided by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) can extend this work by nominating ROIs likely to play a specific role in mediating genetic effects on AD‐related cognitive decline. Nominated ROIs may be suitable targets for biomedical interventions that slow the progression of AD.

Method

Genetic and neuroimaging data were obtained from the ADNI 3 cohort. Amyloid burden measurements (SUVrs) were extracted and intensity‐normalized using the provided whole‐cerebellum reference region SUVr (Landau et al., 2021 ADNI). Imputed genotyping data included 5,402,690 variants from 308 individuals. Genome‐wide association studies predicted FBB changes in each of 68 FreeSurfer cortical ROIs utilizing age, gender, years of education, and the first 10 principal components as covariates. Within each individual imaging feature, FDR‐corrected P value thresholds determined significance (ɑ = 0.05). Mediation analysis combined identified SNP‐imaging feature associations with clinical cognitive score data to determine if changes in amyloid burden mediate genetic effects on clinical outcomes.

Result

149 unique SNPs and 28 unique imaging features were implicated in 881 FBB SNP‐feature associations (P values as low as 8.97e‐9). Although most associations are linked to known AD genes, a number of SNPs on chromosomes 18, 15, 14, 12, 6, 4, and 2 were also identified (Fig 1). Significant GWAS associations were carried forward to identify 83 mediation relationships (Bonferroni P < 1.56e‐6). An especially large number of significant causal mediation relationships implicated the entorhinal cortex and parahippocampal gyri, both of which play a significant role in learning and memory (Fig 2).

Conclusion

Genetic association traced some of the variation in FBB measures of amyloid burden to genetic drivers throughout the genome. Mediation analysis confirms that the FBB measures in the entorhinal cortex and parahippocampal gyri mediate the effects of some genetic findings on learning and global cognition. Future analyses of FBB measures as imaging endophenotypes may inspire pathway analyses and integrate additional clinical or biological information.
Familial FTD in China:progress and prospects
Authors: Chen Qin
Published: December 2023

Background

Frontotemporal dementia (FTD) is a set of clinical syndromes characterized by progressive abnormalities in behavior, executive function, language, with a strong genetic background. However, the familiar FTD studies were rare in China. Here we aim to review the previous cross‐sectional reports of Chinese FTD patients with gene mutations, as well as the update status of the longitudinal familiar FTD study by the Chinese Familial Frontotemporal Lobar Degeneration Consortium (CFFC).

Method

To review current status of Chinese FTD patients with gene mutations, we performed a comprehensive electronic searches of Medline, PubMed, and Embase databases were performed by using the combination of a number of medical subject headings, Emtree subject headings, and free‐text terms (“frontotemporal lobar degeneration” or “frontotemporal dementia” for clinical categories; “Chinese” or “China” for ethnics). To start a multi‐center longitudinal cohort of familiar FTD, we established the CFFC in October 2022 by involving 7 top teaching hospitals across China. Patients with MAPT, GRN and C9orf72 mutations were enrolled and followed up according the designed framework.

Result

Based on the previous reports, genetic mutations accounted for 5.13%‐27.9% as reported in a few cross‐sectional cohort of Chinese FTD patients. Mostly reported pathogenic variants were MAPT, followed by GRN, TBK1, CHCHD10, C9orf72 repeat expansions, VCP, and SQSTM1. Up till now, there were 26 pedigrees with MAPT mutations, 11 pedigrees with GRN mutations and 9 pedigrees with C9orf72 repeat expansions mutations have been enrolled in the longitudinal multi‐center cohort study by CFFC.

Conclusion

The high prevalence of MAPT mutations in Chinese patients with FTD, may implies a genetic heterogeneity between Chinese and other ethnics. Longitudinal studies with larger sample size to modeling the trajectory of biomarkers in genetic mutation carriers for earlier diagnosis and intervention are needed in the future.
Global platform trial design for tau (MAPT) mutation carriers
Authors: Staffaroni Adam M. , Quintana Melanie , Wendelberger Barbara , Tartaglia Carmela , Heuer Hilary W. , Russell Lucy L. , Gendron Tania F , Petrucelli Leonard , Heller Carolin , Wolf Amy , Cobigo Yann , Sanderson‐Cimino Mark E. , Forsberg Leah K. , Kornak John , Cash David M , Boeve Brad F. , Rosen Howard J. , Rohrer Jonathan D. , Boxer Adam L. ,   Frontotemporal Dementia Prevention Initiative (FPI) Investigators
Published: December 2023

Background

Pathogenic mutations in the MAPT (tau) gene cause familial frontotemporal lobar degeneration (f‐FTLD). No disease‐modifying treatments exist. Tau therapeutics being tested in other tauopathies may be suitable candidates, but the small number of identified mutation carriers prohibits traditional clinical trial designs from achieving adequate power. Platform trial designs permit multiple therapies to be tested in parallel and improve power by sharing placebo groups across treatment arms. We evaluate whether a platform design could improve the likelihood of identifying an effective treatment for MAPT mutation carriers.

Method

ALLFTD and GENFI observational data were used to simulate MAPT prevention and early symptomatic clinical trials (CDR®+NACC‐FTLD≤1). Only presymptomatic participants (CDR®+NACC‐FTLD = 0) within 2.5 years of expected symptom onset based on disease progression models (DPM) were included. First, we evaluated the time and sample size required to test five treatments using a platform design compared to sequential randomized control trials. Platform designs assumed a max of three treatment arms at any time, with new arms enrolling upon completion of prior arms. Each arm randomized 60 mutations carriers 3:1 treatment to placebo, with a placebo group shared across arms. Minimum follow up was 1.5 years with common close. Sequential trials assumed 90 participants allocated 1:1 treatment to placebo, with three‐month intervals between trials. Using a platform design, we compared a novel method for testing therapeutic effects using DPMs to account for differential rates of expected progression compared to traditional mixed models for repeated measures (MMRM) tests controlling for baseline CDR®+NACC‐FTLD.

Result

Five treatments could be tested in a platform design using 300 participants (75% treated) over five years, compared to 450 participants (50% treated) over 13 years using traditional, sequential trials. Platform trial simulations indicated that with 80% power, DPM‐based analytic approach could detect a 25% treatment effect, whereas traditional MMRM could only detect a 40% effect.

Conclusion

Platform designs combined with DPM‐based analyses provide a path to testing more treatments with fewer participants. Adequately powered MAPT platform trials are feasible but require a global clinical trial infrastructure.
Longitudinal associations between mild behavioral impairment, sleep disturbance, and progression to dementia
Authors: Mudalige Dinithi M , Guan Dylan X. , Ghahremani Maryam , Ismail Zahinoor
Published: December 2023

Background

Clinical guidelines recommend incorporating non‐cognitive markers into dementia screening to improve detection. Two of these markers are mild behavioral impairment (MBI) and sleep. MBI is a neurobehavioral syndrome capturing later‐life emergent and persistent neuropsychiatric symptoms, which represent a change from longstanding behavior or personality, as a high‐risk group for incident cognitive decline and dementia. Sleep disturbances include difficulties initiating and maintaining sleep, are common in older adults and are associated with greater risk for dementia. We investigated the longitudinal associations between MBI and sleep disturbance and their association with incident dementia.

Methods

Data were obtained from the National Alzheimer’s Coordinating Center. MBI was derived from Neuropsychiatric Inventory Questionnaire (NPI‐Q) based on a published algorithm. The presence of sleep disturbance was obtained from the NPI‐Q nighttime behaviors item. Cox proportional hazard regressions, adjusted for age, sex, education, and cognitive diagnosis, were used to determine the associations between 1) baseline MBI and incident sleep disturbance (n = 8348); 2) baseline sleep disturbance and incident MBI (n = 9679) and 3) baseline sleep disturbance, with and without concurrent MBI, and incident dementia (n = 12296).

Results

Demographics are summarized in Table 1. As per Table 2, the rate of developing sleep disturbance was 3.3‐fold higher in older adults with MBI at baseline compared to those without MBI (95%CI: 2.96‐3.67; p<0.001). Likewise, the rate of developing MBI was 2.1‐fold higher in older adults with baseline sleep disturbance compared to those without sleep disturbance (95%CI: 1.84‐2.36, p<0.001). The incidence rate of dementia was 2.23‐fold greater in older adults with both MBI and sleep disturbance, relative to sleep disturbance alone (95%CI: 1.65‐3.00; p<0.001).

Conclusions

In this group of dementia‐free older adults, we found a bidirectional relationship between MBI and sleep disturbance. Sleep disturbance was more strongly associated with incident dementia when co‐morbid with MBI. This relationship might suggest a common etiology for MBI and SD, as both were linked with incident dementia. Thus, including both sleep disturbance and MBI into modeling may improve dementia prognostication. Future studies should incorporate biomarkers and additional clinical markers for Alzheimer’s disease and other neurodegenerative disease into the modeling to better understand these relationships.
Understanding synaptic loss in PSP brains with UCB‐J
Authors: Scarpa Miriam , Kumar Amit , Nordberg Agneta K
Published: December 2023

Background

Progressive supranuclear palsy (PSP) is a 4R‐tauopathy causing problems with balance, movement, vision, speech, and swallowing. There is a lack of biomarkers for PSP, which often leads to misdiagnosis, prescription of incorrect pharmacological treatments and likely underdiagnosis. Synaptic vesicle protein 2A (SV2A) PET‐tracer UCB‐J has shown great promise in imaging synaptic loss in many neurodegenerative diseases in vivo including PSP. UCB‐J‐PET imaging holds great potential for the early and accurate diagnosis of PSP, however, there is a substantial gap in knowledge around the extent of synaptic loss in PSP. Hence, it is of utmost importance to investigate synaptic changes in PSP brains with UCB‐J and to establish its correlation with other synaptic and neuropathological markers to gain a deeper understanding of underlying mechanisms for future biomarker validation.

Method

We performed specialized postmortem brain imaging (small and large frozen brain autoradiography) and radioligand binding assays (saturation, competition, and regional distribution), alongside immunohistochemistry and biochemical analyses in PSP and control (CN) brains.

Result

Saturation studies in brain homogenates (BH) from the frontal cortex (FC) showed lower specific binding of 3H‐UCB‐J in PSP (Bmax: 348‐409 fmol/mg, Kd∼2.7nM) as compared to CN brains (Bmax:0.4‐0.5 pmol/mg, Kd∼3.5nM), indicating a loss in SV2A. Importantly, PSP brains showed much higher 3H‐UCB‐J specific binding in nuclear membrane P1‐fractions (Bmax 18.7‐22.1 pmol/mg, Kd ∼3.0nM) and synaptosomal‐membrane P2‐fractions (Bmax: 10.3‐12.3 pmol/mg, Kd∼2.4nM) as compared to BH (see above). Small section autoradiography showed lower 3H‐UCB‐J specific binding in PSP FC, but unexpectedly higher average specific binding in globus pallidus as compared to CN, suggesting regional differences and potential interaction with other brain tissue components/proteins.

Conclusion

Our findings clearly demonstrate that there are region‐specific changes in UCB‐J binding in PSP brains compared to CN and further reflect the need for its in‐depth validation in postmortem brains and correlation with other synaptic and neuropathological markers. Moreover, P2 fraction is most optimal for reflecting synaptic loss with UCB‐J. The ongoing regional distribution, biochemical and immunostaining studies will help elucidate changes in synaptic integrity in PSP.