bluuebunny/crossref_metadata_2025 huggingface dataset:
Synaptic oligomeric Tau is an early event in tau‐affected brain regions in Alzheimer’s disease.
Authors: Dolcet Sònia Sirisi , Colom‐Cadena Martí , Querol‐Vilaseca Marta , Rose Jamie , Sánchez‐Aced Érika , Andrian Teodora , Pujals Sílvia , Horrocks Mathew , Lleó Alberto , Spires‐Jones Tara L
Published: December 2022

Background

Deposition of fibrillar forms of tau‐neurofibrillary tangles (NFT) and neuropil threads (NT) follow a progressive pattern across brain regions as reflected by Braak stages. However, oligomeric forms of tau have been proposed to precede the appearance of fibrillar forms. Synapses are the earliest structure linked to Azheimer’s Disease cognitive loss, but whether tau pathology, fibrillar or oligomeric affects early this structure in each region remains unclear. This is mainly explained by the technical limitations to study oligomeric forms of tau and the visualization of synaptic terminals. We aim to investigate the presence of oligomeric tau at synapses of human AD cases and its relation to the presence of fibrillar forms of tau in different brain regions.

Method

We used array tomography microscopy to visualize single synaptic terminals on postmortem human samples from BA20/21 and BA17 brain regions of 10 AD and 10 controls with diverse Braak stages. Pre‐ and post‐synaptic terminals (synaptophysin and PSD95) and oligomeric tau (T22 antibody) were labelled. To compare synaptic tau with total fibrillar tau burden, NFTs and NTs were quantified from immunohistochemical sections (AT8 antibody) of the same cases and areas. We also studied the presence of tau in synapses using Western Blot experiments in synaptoneurosomes enriched fractions from the same cases and areas (Tau5 antibody). Finally, the presence at synapses of oligomeric and fibrillar tau was confirmed with other superresolution techniques such as electron microscopy, STORM and DNA‐PAINT.

Result

We found that 1) Oligomeric tau was found in both pre‐ and postsynaptic terminals, in a higher proportion of presynaptic terminals. 2) Oligomeric tau at synapses was found in areas without abundant fibrillar forms of tau. 3) A higher proportion of oligomeric tau when compared to phosphorylated tau was found at synaptic terminals in early affected cases. 4) Early synaptic oligomeric tau was found also by western blot of synaptoneurosomes, electron microscopy and STORM.

Conclusion

Our results suggest that synaptic oligomeric tau may be an early event at tau‐affected brain regions, preceding the phosphorylation of tau and the formation of fibrillar forms. Also, the findings may support the transsynaptic spreading of tau at early stages.
The presence of disease‐associated tau leads to adverse effects on the autophagy and endolysosomal pathway in a cell model of tauopathy
Authors: Pollack Saskia J , Dakkak Dina , Guo Tong , Gómez‐Suaga Patricia , Noble Wendy , Hanger Diane P
Published: December 2022

Background

Dysfunctions in the autophagy and endolysosomal pathways have been reported in Alzheimer’s Disease and related tauopathies. The presence of disease‐associated tau itself may play a role in damaging these pathways leading to its altered clearance. Minimal expression of a disease‐associated truncated tau species (Tau35) in mice results in a progressive tauopathy phenotype, including increased tau phosphorylation, cognitive and behavioural abnormalities and impaired protein clearance. In this study, we sought to explore the effects of Tau35 on the autophagy and endolysosomal pathway in cultured cells expressing Tau35 and from Tau35 mice.

Method

Chinese hamster ovary (CHO) cells stably expressing Tau35 (CHO‐Tau35) or full‐length human 2N4R tau (CHO‐FL) were generated. Primary cortical neurons from Tau35 transgenic and wild‐type mice were isolated and cultured for 14 days in vitro (DIV). Cells were fixed for immunocytochemistry or lysed to isolate protein/RNA for western blotting and RT‐qPCR to detect the effect of Tau35 expression on autophagy and lysosomal‐related proteins and genes.

Result

CHO‐Tau35 cells exhibited a marked reduction in several autophagy and lysosomal‐related markers, including LC3‐II, LAMP2 and cathepsin D. CHO‐Tau35 cells also accumulated lipid droplets and showed disruptions in mammalian target of rapamycin complex 1 (mTORC1) activity and autophagic flux. Moreover, Tau35 expression also resulted in alterations in early endocytic markers, including EEA1. Similar reductions in autophagic and endosomal markers were observed in primary cortical neurons cultured from Tau35 mice. Notably, the nuclear translocation of transcription factor EB (TFEB), a key mediator of lysosomal biogenesis, as well as the transcription of several TFEB‐target genes, was significantly reduced in both CHO‐FL and CHO‐Tau35 cells.

Conclusion

Our findings suggest that disease‐associated truncated tau damages the clearance of cellular proteins and reduces TFEB‐mediated lysosomal biogenesis. Investigating whether autophagy is disrupted due to tau‐induced lysosomal dysfunction may lead to the identification of novel therapeutic targets for dementia.
APOE4 Impairs Microglia Response to Neurodegeneration in Alzheimer’s Disease
Authors: Rosenzweig Neta , Yin Zhuoran , Madore Charlotte , Butovsky Oleg
Published: December 2022

Background

APOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). We previously identified that APOE signaling governs the transcriptional regulation from homeostatic to neurodegenerative microglia (MGnD). However, the underlying mechanism for APOE4‐mediated microglial dysregulation and its contribution to increased risk for developing AD, is unknown.

Method

Here we aimed to dissect the impact of microglial APOE4 on AD pathology, using CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl:APP/PS1.

Result

We identified reduced numbers of Clec7a+ MGnD‐microglia per plaque in APP/PS1:APOE4‐KI mice, despite their increased plaque load, compared with APP/PS1:APOE3‐KI mice. Moreover, APOE4‐KI mice challenged with labeled apoptotic neurons, failed to respond to acute neurodegeneration, depicted by reduced numbers of phagocytic MGnD‐microglia at injection site compared with APOE3‐KI mice. Here we show that conditional genetic deletion of APOE4 in microglia resulted in increased numbers of MGnD‐microglia in response to acute neurodegeneration and in APP/PS1 mice. scRNAseq analysis showed increased proportion of MGnD‐microglia in APP/PS1:APOE4 conditional KO mice, associated with reduced plaque pathology and increased astrocytic recruitment towards plaques. Furthermore, we show impaired induction of MGnD signature in AD brains of APOE4 carriers.

Conclusion

Our findings show that APOE4 is a negative regulator of MGnD‐microglia in AD, and that its genetic deletion restores the induction of MGnD signature associated with reduction in plaque pathology. Taken together, these findings identify a cell‐intrinsic role of APOE4 in the induction of dysfunctional MGnD microglia and their impaired response to neurodegeneration, which may provide new molecular targets to modulate and restore functional microglia in AD.
Potential for Re‐Identifying Brain PET Research Participants using Face Recognition
Authors: Schwarz Christopher G. , Kremers Walter K. , Lowe Val J. , Savvides Marios , Gunter Jeffrey L. , Senjem Matthew L. , Vemuri Prashanthi , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Jack Clifford R.
Published: December 2022

Background

Studies of aging and dementia often acquire brain MRI and PET images, then de‐identify and share these widely with other researchers. It is known that research participants can potentially be re‐identified from brain MRI and CT using face recognition, but this has not been tested with PET imaging.

Method

We generated face reconstruction images of 182 volunteers using their existing amyloid (PiB), tau (FTP), and FDG PET scans from clinical GE PET/CT scanners, and we measured how often commercial automatic face recognition (Microsoft Azure) correctly matched these reconstructions with photographs of their faces. We additionally compared these match rates with face reconstructions from CT (from PET/CT) and MRI. When testing face recognition from PET scans, CT was used only during PET reconstruction, not for face recognition. We also validated our updated mri_reface software, originally developed to de‐identify (“de‐face”) faces in MRI, with new support for PET images. We measured face recognition rates before and after applying mri_reface to PET, CT, and MRI. In addition, we measured effects of de‐facing on biomarker measurements (global and regional SUVR) using 244 ADNI Florbetapir (FBP) amyloid PET scans with two automated pipelines: FreeSurfer 6.0 (PETSurfer) and an in‐house SPM12‐based pipeline.

Result

Rates of successful face recognition with PET ranged from 32‐41% (Table 1) across tracers. These were lower than MRI (98%) and CT (78%) but still concerning for participant privacy. Using mri_reface reduced face recognition to 0‐3.5% for PET, 5% for CT, and 8% for MRI. mri_reface had little effect on global amyloid SUVR measurements from ADNI PET images (Figure 1). ICC values between original and de‐faced images were 1.00 with biases and median absolute differences < 0.5%, across both pipelines. Effects on individual regions all had ICC values > 0.98 with biases and median absolute differences < 2%.

Conclusion

Face reconstructions from PET images have sufficient quality for potential re‐identification using publicly available face recognition technology. Research studies should consider using face de‐identification (de‐facing) software on PET images in addition to CT and structural MRI. Our free, automatic mri_reface software greatly reduced the potential for face recognition without substantially affecting SUVR measurements.
Dual tasking paradigm in clinical stages of early Alzheimer’s disease
Authors: Sorinas Jennifer , Cormack Francesca K , Taptiklis Nick , Vallejo Vanessa , Snædal Jón , Hannesdottir Kristin , Curcic Jelena
Published: December 2022

Background

In Alzheimer’s disease (AD) both motor and cognitive domains are impaired [1‐2]. However, these domains are usually assessed independently and even when performing dual‐task (DT) paradigms, the cognitive‐motor interaction (CMI) is not taken into account, which may lead to misinterpretation of the patient’s global state. To date, there are no precise markers to detect subtle signs of pre‐clinical neurodegeneration or to accurately monitor disease progression.

Method

We have evaluated the motor and cognitive components of a DT paradigm concurrently (Figure 1) with the aim to identify a sensitive marker of early AD. Fifty participants, aged 60 to 80 years, were included in the study and distributed across four cohorts of early AD [3]: 1) amyloid negative, cognitively healthy participants (control group), 2) amyloid positive pre‐symptomatic AD, 3) Mild Cognitive Impairment (MCI) due to AD and 4) mild AD. Two inertial gait measurement units (IMUs) (Physilog, GaitUp S.A.) were attached to each foot and a small wearable microphone (Wireless GO, RØDE) was used to record counting. Both timing [4] and gait features were extracted from raw data. Correct response rate (CRR) and gait speed were used to evaluate the CMI based on Plummer’s classification system [5]. Moreover two‐way ANOVA was carried out to evaluate the effect of cohort and cognitive load conditions on the CMI.

Result

Our results show that there is a significant drop in both cognitive and motor performance while performing DT and that this drop is more pronounced with increased disease severity and as we increase the cognitive load of the task (Figure 2). Moreover, CMI shows a cognitive‐priority trade‐off in all cohorts (better/stable counting performance while walking becomes slower). However, when the cognition load is increased, in particular in more severe stages of disease, this shifts towards a mutual interference effect, i.e. where both counting performance declines and walking slows down (Figure 3).

Conclusion

To our knowledge, this is the first feasibility study assessing the CMI at preclinical and early clinical stages of AD. Our preliminary results suggest that the DT paradigm is a sensitive method to detect early signs of neurodegeneration and monitor AD progression.
Neurophysiologic Correlates of Preclinical Alzheimer's Disease
Authors: Manning Daniel , Morse Christie , Northrop Andrew , Zeng Victor , Bolo Nicolas , Shaughnessy Lynn , Baratono Sheena , Buss Stephanie S. , Ozdemir Recep , Shafi Mouhsin , Fried Peter J.
Published: December 2022

Background

Alzheimer’s disease (AD) is associated with neurophysiologic changes, including cortical hyperexcitability and reduced long‐term potentiation (LTP)‐like plasticity, that can be investigated using transcranial magnetic stimulation (TMS). AD is preceded by a preclinical phase of beta‐amyloid accumulation without clinical or cognitive symptoms. Our goal is to test the relationship of TMS‐based neurophysiologic markers against established cognitive and MRI‐based measures of preclinical AD. If neurophysiologic changes precede the clinical manifestation of AD, they could serve as prognostic markers and targets for therapeutic interventions to slow its progression.

Method

Data was acquired from eight cognitively unimpaired older adults (three females, ages 65‐78 years) as part of an ongoing study (BrightFocus™ Foundation‐A2021288S, IRB#‐2020P000889). Cognition was evaluated with the 5‐item Preclinical Alzheimer’s Cognitive Composite (PACC5), which is sensitive to early AD‐associated decline. Global cortical atrophy was assessed from MRI as the mean thickness across the AD Cortical Signature Network (ACSN)—regions showing morphologic changes that precede the clinical manifestation of AD. Cortical excitability was assessed as the average amplitude of TMS‐evoked EEG potentials (TEPs) elicited from TMS to motor cortex, while LTP‐like cortical plasticity was assessed as the change in TEPs following intermittent theta‐burst stimulation (iTBS). The strength of associations between the neurophysiologic, imaging, and cognitive measures were performed using non‐parametric Spearman Rho coefficients.

Result

Spearman coefficients revealed a large association between reduced cortical thickness (more atrophy) and worse cognition (Rho=0.71), as expected. Higher excitability (larger TEPs) showed a large association with worse cognition (Rho=‐0.54) and a small association with reduced cortical thickness (Rho=‐0.29). Lower cortical plasticity (smaller change in TEPs post‐iTBS) showed a medium association with worse cognition (Rho=0.46) and a large association with reduced cortical thickness (Rho=0.86).

Conclusion

In cognitively unimpaired older adults, TMS‐EEG measures of cortical excitability and LTP‐like plasticity are strongly correlated, respectively, with cognitive and MRI‐based markers of Preclinical AD. These finding suggest cortical hyperexcitability and reduced LTP‐like plasticity, which are present in AD, may occur before its clinical manifestation. If these results are confirmed in a larger cohort with biomarker testing, these markers could help prognosticate the development of AD symptoms and serve as targets for therapeutic intervention.
Early accumulation of Aβ and Tau is associated with increase in cortical thickness
Authors: Hojjati Seyed Hani , Habeck Christian , Butler Tracy A , RoyChoudhury Arindam H , Luchsinger Jose A , Devanand Davangere P. , Stern Yaakov , Razlighi Qolamreza
Published: December 2022

Background

There is no consensus in the field regarding the relationship between AD pathologies (Aβ, and Tau) and neurodegeneration. One reason that may contribute to this disagreement is the definition of cut‐point to categorize participants with or without significant pathologies. This approach overlooks an important early stage of pathological accumulation. In this study, we take advantage of Florbetaben/MK6240 PET scans from 61/21 young (<40) and healthy participants to redefined the cut‐point of Aβ/Tau uptake and investigate their association with cortical thickness as a measurement of neurodegeneration.

Method

To capture the early effect of pathologies, we quantify global pathologies by averaging AD‐related regions uptake; global Aβ: frontal, parietal, temporal, anterior and posterior cingulate, and precuneus, global Tau: fusiform, amygdala, parahippocampal, entorhinal, inferior temporal, middle temporal, and medial temporal lobe (MTL) Tau: entorhinal and parahippocampal. We redefied the cut‐point of AD pathologies using 95% percentile of the fitted normal distribution to the young subject's uptakes. Using newly defined cut‐points (1.01<global Aβ<1.25, 0.72<global Tau<1.15, and 0.66<MTL Tau<1.11), we identified 232 older participant (64.79±3.55, 94 males, 229 HC) from 394 healthy control (HC) and 52 with mild cognitive impairment (MCI). To assess the relationship between AD pathologies and neurodegeneration, we run a multiple regression to model cortical thickness at each vertex in the identified elders with global Aβ, and global Tau controlling for age, gender, and Intracranial volume (ICV).

Result

Early and low accumulation of Aβ and Tau were associated with higher cortical thickness in many regions throughout the cerebral cortex. More interestingly, MTL (where the early Tau deposition occurs) was among the regions showing a positive association with Aβ deposition and cortical thickness.

Conclusion

These results, provide preliminary evidence that early and low accumulations of AD pathologies are associated with higher cortical thickness. Our results may shed some light on the discrepancies between the existing studies investigating the same relationship. As it has been recently hypothesized, it suggests that the cascade of events in AD may start much earlier than what had been considered in the field and this early accumulation of Aβ and Tau has completely different consequences on brain structure/function.
Association of Delirium with Long‐term Cognitive Decline: An Update
Authors: Goldberg Terry E. , Wang Yuanjia , Hua May , Garcia Paul , Whittington Robert A , Moitra Vivek
Published: December 2022

Background

Delirium has been associated with a variety of unfavorable outcomes, including increasing length of stay in the hospital, poor functioning, and death. We compiled the literature and conducted a meta‐analysis (Goldberg et al, JAMA Neurol, 2021) in order to determine if delirium was also associated with long term cognitive decline. Twenty‐three studies that included over 3500 delirium and 6900 control patients were included in the meta‐analysis. Cognitive assessments were conducted on average at 2.3 years after the episode of delirium. We found that the overall effect size G was .45 (P<.001) indicating that patients who experienced delirium performed significantly worse than controls who did not experience delirium.

Method

We will search the literature on cognitive changes after delirium from Jan 1, 2019 onward. We will include all relevant studies with the same inclusion criteria as our prior study (namely an episode of delirium, cognitive assessment 3 or more months after the episode, and a control group). We will then compute the effect size G for each individual study in order to determine if the values are consistent with our previous findings. We will also examine if delirium meets Bradford Hill criteria for playing a causal role in cognitive decline in association studies.

Second, we will review the literature on cognitive changes after delirium in individuals experiencing SARS‐CoV‐2 infection, given the many reports of patients experiencing delirium in the ICU while ventilated. We will derive G for these studies, so long as they incorporate a control group that adjusts for disease severity and virus positivity.

Result

We will present results of this new review in terms of G for individual studies, overall G when these are added to the original meta‐analysis, and a Bradford Hill criteria checklist. For delirium after SARS‐Cov‐2 infection we will rely on a narrative description.

Conclusion

First, we will examine trends in reports of the magnitude cognitive changes after delirium over the past three years, as well as examine if newer or more comprehensive methodologies are being deployed. Second, we will examine the extent of cognitive changes after delirium in the context of severe COVID‐19.
MicroRNA‐502‐3p regulates the GABAergic synapse function in Alzheimer’s disease
Authors: Kumar Subodh
Published: December 2022

Background

Alzheimer’s disease (AD) is most common dementia in the aged individuals. Synapse dysfunction is the early event in the brain that initiate AD progression. Studies found the reduced inhibitory GABAergic synapse function in AD subjects.

Methods

Global microRNA (miRNA) affymetrix analysis was performed on synaptosomal fractions from AD subjects and cognitively normal individuals. In silico analysis and luciferase assays were performed to confirm the miR‐502‐3p binding at the GABRA1 mRNA. MiR‐502‐3p agomiRs (overexpression) and antagomiRs (suppression) studies were performed on mouse primary hippocampal (HT22) neurons. The GABA receptor functions were accessed by electrophysiology studies using patch clamp analysis.

Results

Our global microRNA (miRNA) affymetrix study of synaptosomal fraction identified miR‐501‐3p/miR‐502‐3p as potential miRNAs. Data analysis showed the higher expression of miR‐502‐3p in the AD synapse relative to cognitively healthy synapse. On the other hand, Gamma‐Aminobutyric Acid Type A Receptor Subunit Alpha1 (GABRA1) levels were found to be reduced in AD synapse. In silico analysis and luciferase assay confirmed that miR‐502‐3p binds to multiple sites at the GABRA1 mRNA and suppresses its translation. In vitro studies using mouse primary hippocampal (HT22) neurons unveiled that miR‐502‐3p agomiRs (overexpression) decreased HT22 cell survival and antagomiRs (suppression) treated cells showed improved cell survival. qRT‐PCR, immunoblotting and immunostaining analysis conformed the reduced levels of GABRA1 by miR‐502‐3p overexpression, while suppression of miR‐502‐3p increases the GABRA1 protein levels. Further, electrophysiology studies using patch clamp analysis showed reduced GABA receptor functions and impaired chloride ion (Cl−) channel by over expression of miR‐502‐3p. On the other hand, reduced expression of miR‐502‐3p showed increased GABA receptor functions and Cl− influx into the cells.

Conclusion

Our initial observations confirmed that miR‐502‐3p modulate GABRA1 receptor functions. Therefore, miR‐502‐3p could be a therapeutic target to improve the GABAergic synapse function in AD.
Cognitive decline in Autosomal Dominant Alzheimer’s Disease and its relation to TauPET and fMRI Complexity in the Hippocampus
Authors: Jann Kay , Cen Steven Y , Ringman John M , Wang Danny JJ
Published: December 2022

Background

In recent years the neurofibrillary tangle pathology detected with tauPET imaging has been found to be closely related to cognitive decline in Alzheimer’s Disease. However, PET scans are expensive and involve radioactive tracers. We and others have proposed the complexity of rs‐fMRI using MultiScaleEntropy (MSE) as an index for neuronal function. Reduced entropy values have been associated with aging, APOEɛ4 genotype and cognitive function in AD. Here we hypothesize that the BOLD signal complexity is sensitive to tau‐related neuronal injury and cognitive decline in AD.

Method

Data (N=44, Table1) was obtained from the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study, which examines persons at‐risk for autosomal‐dominant AD. All subjects had T1, tauPET (18F‐AV1451) and two resting‐state fMRI scans. FMRI data underwent standard preprocessing before computing MSE. SUVR images were calculated with inferior cerebellum as reference region. Correlations between SUVR tauPET and MSE were calculated voxel‐wise including age, gender and gray ‐matter volume as covariates. Mediation effects in hippocampal clusters between MSE, tauPET and cognitive function (MMSE) were tested in SAS (95% confidence‐interval was estimated with 1000 bootstrapping samples).

Result

We observed gradually decreasing entropy and gradually increasing tauPET from NC to MCI and AD (Fig1). This inverse relationship was significant (p<0.05,corrected) in hippocampus, lateral temporal lobe and anterior cingulate cortex (Fig2). Mediator analysis revealed significant indirect (mediation) effects of PET to the association between MSE and MMSE (log‐transformed) in both hippocampi: Left: total 1.37 95%CI (0.6,2.14) indirect 0.86(0.27,1.85) and Right: total 1.49(0.66,2.31) indirect 1.04(0.48,1.84).

Conclusion

Our findings show that there is a statistically significant total effect between MSE and cognitive decline that is largely mediated by tauPET, with 63% and 70% of total effect for right and left hippocampus respectively. These results support the relevance of hippocampal tauopathy on cognitive decline. Moreover, complexity of rs‐fMRI is associated with both regional tau protein accumulation and cognitive decline, and thus could provide a safe and cost‐effective alternative marker for regional neuropathology and prediction of cognitive decline in AD.
Short‐term cognitive practice effects and their relation to amyloid and tau in preclinical Alzheimer’s disease
Authors: Young Christina B , Mormino Elizabeth C. , Papp Kathryn V.
Published: December 2022

Background

Identification of cognitive paradigms that relate to biomarker evidence of Alzheimer’s disease (AD), such as tau, can greatly enhance patient selection for clinical trials. Computerized cognitive assessments that can be frequently administered may yield multiple unique variables that can improve detection of subtle cognitive decline in preclinical AD. Indeed, practice effects (i.e., improved performance on repeated testing) are diminished in clinically unimpaired older adults with abnormal amyloid, but their relations with tau are unknown. Here, we determine whether baseline performance and practice effects at 3 months re‐testing on the Computerized Cognitive Composite (C3) relate to medial temporal lobe (MTL) tau.

Method

We examined 390 clinically unimpaired older adults from the A4 study with tau PET (flortaucipir) imaging who completed two C3 assessments pre‐study randomization. C3 assessments were completed approximately 90 days apart and included pattern separation [Behavioral Pattern Separation Test – Object (BPS‐O)], associative memory [Face Name Associative Memory Exam (FNAME)], and visual memory [One‐Card Learning (OCL)]. C3 baseline performance and practice effects (change in performance from Assessment 1 to 2) were examined in relation to continuous amyloid and MTL tau burden.

Result

Greater amyloid burden was significantly associated with lower baseline C3 scores (B(SE) = ‐0.86 (0.24), p<0.001) but not C3 practice effects (B(SE) = ‐0.09 (0.23), p = 0.702). In contrast, greater tau in the MTL was significantly associated with reduced C3 practice effects (B(SE) = ‐0.49 (0.21), p = 0.023) and marginally associated with baseline C3 performance (B(SE) = ‐0.37 (0.22), p = 0.099) while controlling for continuous amyloid and demographic variables. Further examination of C3 subtests revealed that pattern separation (BPS‐O; B(SE) = ‐0.70 (0.34), p = 0.039) and associative memory (FNAME; B(SE) = ‐1.13 (0.42), p = 0.007) were driving MTL tau associations with C3 practice effects.

Conclusion

Diminished practice effects on memory‐based measures are associated with elevated MTL tau burden in preclinical AD. Furthermore, diminished practice effects offer a unique signal above and beyond cross‐sectional performance. For clinical trials, examination of practice effects on computerized assessments over a short timescale may be a cost‐effective method to facilitate identification of those with biomarker evidence of AD.
Examining the cognitive performance of older adults in urban and rural regions of India.
Authors: Arora Sonakshi , Wong Christina G.
Published: December 2022

Background

Aging population is rapidly growing in India, with the majority of the older adult population residing in rural regions. Studies globally show a higher prevalence of cognitive impairment in rural regions than urban. With the lack of research on aging in India, there is an urgent need to evaluate the cognitive health of older adults in India to allow for their care needs to be met appropriately and promote healthy aging.

Method

This study used data from Harmonized Longitudinal Aging Study of India, Diagnostic Assessment of Dementia (LASI DAD), which was developed by the Gateway to Global Aging Data. The sample size was nationally representative (n = 4096) of older adults aged 60 years and above in India (urban community = 1561, rural village = 2535). Given the heterogeneity of the population, adapted cognitive instruments were used. This study assessed if geographical residency (urban vs. rural) of older adults influenced their cognitive performance above and beyond demographic factors (i.e., age and gender) and education using a hierarchical regression in SPSS.

Result

18% of the variance in cognitive performance was accounted for by age and gender. 37% of the variance in cognitive performance was accounted for by the addition of education. Finally, geographic residency accounted for 1.2% of the variance in cognitive performance of older adults. Older adults living in rural villages had statistically significantly lower cognitive performance than older adults living in urban communities (B = ‐.218, p < 0.01). Women’s cognitive performance was lower than men’s (B = ‐.229, p <0.01).

Conclusion

The geographic residency only accounted for a small proportion of variance in the cognitive performance of older adults in India. The majority of the disparity was accounted for by education, with older adults with higher education performing better. Despite that, older adults living in rural villages performed worse on cognitive measures than older adults living in urban communities. Older women performed worse than men. The contribution of factors such as depression, socioeconomic status, and cardiovascular health to the cognitive health of older adults in India should be explored further.
The potential contribution of the adaptive immune system in frontotemporal dementia
Authors: Eid Abdulmunaim M , Pascual Maria B , Masdeu Joseph C. , Appel Stanley H , Faridar Alireza
Published: December 2022

Background

Inflammation is a significant component of neurodegenerative disorders including frontotemporal dementia (FTD). Co‐localization of neuroinflammation and brain protein aggregation with tau and TDP‐43 has been previously documented in the clinical setting of FTD. However, the role of the adaptive immune system particularly regulatory T cells (Tregs) is not clearly defined. We hypothesize that Tregs immunomodulatory mechanisms are compromised and shift the immune system towards a proinflammatory status which might contribute to disease progression.

Method

24 FTD patients and 11 age‐matched healthy controls were recruited by the Houston Methodist Nantz National Alzheimer’s Center (NNAC). Venous blood was processed for multicolor flow cytometry to assess the phenotype of Tregs. Tregs were also co‐cultured with corresponding responder T cells (Tresps) in various ratios and proliferation of Tresps was determined by 3H‐thymidine incorporation. Plasma assays of 48 cytokines were obtained through Olink® Target 48 Cytokine panel for FTD patients and age‐matched healthy controls and comparisons were made.

Result

The suppressive function of Tregs on corresponding Tresps proliferation was significantly compromised in both 1:1 (P = 0.034) and 1/2:1 (P = 0.024) Tregs:Tresps ratios. In immunophenotypic analyses, no differences were detected between FTD patients and controls regarding percentages of Tregs, Tresps, CD8+ T cells, or natural killer cells (NKC). The Olink® analysis revealed increased plasma levels of pro‐inflammatory cytokines and chemokines in FTD patients including CXCL9, CXCL10, CXCL11, and TNFα.

Conclusion

Regulatory T cells immunomodulatory function is compromised in patients with FTD, indicating a shift of peripheral immune cells towards an increased pro‐inflammatory state. In addition, there is upregulation of plasma chemokines CXCL9, CXCL10, CXCL11, which promote immune cell recruitment to CNS sites of inflammation. Combining these two key findings, we propose that pro‐inflammatory peripheral immune cells contribute to neuroinflammation and possibly disease progression in FTD.
Sleep disorders and incident dementia: a nationwide observational cohort study
Authors: Damsgaard Line , Janbek Janet , Laursen Thomas Munk , Erlangsen Annette , Spira Adam P. , Waldemar Gunhild
Published: December 2022

Background

In recent years, significant research efforts have focused on identifying modifiable risk factors to be leveraged for dementia prevention. Sleep is required for memory consolidation and normal brain functioning, and various mechanisms are proposed between poor sleep quality and cognitive impairment. Several studies have examined the role of sleep disturbances as a risk factor for dementia; however, most of these studies have involved smaller cohorts and short time intervals, and often rely on retrospective surveys and self‐reported exposure data. Our aim was to examine the association between sleep disorders and late‐onset dementia in an entire population.

Method

In a nationwide cohort with a 40‐year follow up, we linked nationwide population data with information on hospital‐based sleep disorder diagnoses and late‐onset dementia from the extensive Danish health registers. Incidence rate ratios (IRR) were calculated using Poisson regression analysis. Analyses were adjusted for age, sex, calendar year, education, and somatic and psychiatric comorbidities.

Result

The cohort consisted of 1,491,276 people. Those with any hospital‐diagnosed sleep disorder had a 17% higher risk of dementia (IRR 1.17, 95% CI 1.11‐1.24) compared to people with no sleep disorder diagnosis. The highest risk was found for men with ‘other specific disorders’ (e.g. insomnia, hypersomnia, non‐organic sleep disorders) with an IRR of 2.00 (95% CI 1.71‐2.32). The risk of dementia was significantly increased 0 to 5 years after sleep disorder diagnosis (IRR 1.35, 95% CI 1.25‐1.47), while the association after 5 years or more was non‐significant (1.05, 95% CI 0.97‐1.13).

Conclusion

Our findings indicate an increased short‐term risk of dementia following a hospital‐based sleep disorder diagnosis, while we found weaker evidence of a long‐term risk. While this may indicate that sleep disorders could be early symptoms of dementia as well as a risk factor, further research is needed to evaluate sleep disorders as potential early symptoms of dementia, risk factors for dementia, or both, and characterize how this may change at different points along the dementia course. Increased knowledge of the role of sleep disorders in dementia could help inform efforts towards diagnosing dementia in the early stages of the disease or even in dementia prevention.
Neuroinflammation in posterior cortical atrophy and typical Alzheimer’s disease
Authors: Abdi Zeinab , Yong Keir X X , Crutch Sebastian J , Schott Jonathan M , Lashley Tammaryn
Published: December 2022

Background

Posterior cortical atrophy (PCA) is a neurodegenerative, predominantly young‐onset syndrome most commonly caused by Alzheimer’s disease (AD). PCA presents with visual and spatial dysfunction attributed to occipito‐parietal or “posterior” brain regions rather than memory difficulties characteristic of typical Alzheimer’s disease (tAD) attributed to medial temporal regions. Whilst the underlying pathology of PCA and tAD are usually the same: Aβ plaques and tau neurofibrillary tangles (NFTs), imaging and neuropathological work points to a more posterior distribution of NFTs in PCA. Differences in inflammatory response have been proposed to relate to AD heterogeneity evident in PCA. This study compared neuroinflammation between PCA and tAD in relation to Aβ and tau at autopsy.

Method

Immunohistochemistry for microglial markers (CD68, Iba1, HLA‐DR/DP/DQ) and Aβ/tau was carried out on the frontal, parietal, temporal and occipital brain regions of 26 clinically and pathologically phenotyped PCA cases and 27 age and gender‐matched tAD cases from UCL Queen Square Brain Bank. All PCA patients had a neuropathological diagnosis of AD (Table 1). Marker load was quantified as percentage surface area of the 4 brain regions using Image J software.

Result

This study showed significantly lower temporal CD68 load in the tAD compared with the PCA group, (reduced CD68% area: ‐ 0.88%; (95%CI [‐0.42,‐1.34]), p<0.001). Frontal CD68 load was significantly lower in PCA compared with tAD, (reduced CD68% area: ‐0.54; (95%CI[‐1.01,‐0.07]), p = 0.025), see Fig 1A. Parietal tau was significantly higher in the PCA group compared with the tAD group (increased tau % area: 5.15%; (95% CI [0.55, 9.76]), p = 0.029. The highest observed tau load within the PCA group was in the frontal region and for tAD in the temporal region, see Fig 1B.

Conclusion

Regional increases in tau and decreases in markers of activated microglia differ between PCA and tAD. Discrepancies between tau and activated microglial markers are particularly apparent in temporal and frontal regions in tAD and PCA respectively. This may be in line with the notion of a disconnect between microglial phagocytic activity at later stages of Alzheimer’s disease leading to further accumulation of tau and subsequent neuronal death.
Functional eigenvector centrality dynamics are related to amyloid deposition in preclinical Alzheimer’s Disease
Authors: Lorenzini Luigi , Ingala Silvia , Collij Lyduine E. , Wottschel Viktor , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Chetelat Gael , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Waldman Adam , Wardlaw Joanna M , Ritchie Craig W. , Gispert Juan Domingo , Mutsaerts Henk‐Jan , Visser Pieter Jelle , Scheltens Philip , Tijms Betty M. , Barkhof Frederik , Wink Alle Meije
Published: December 2022

Background

In preclinical Alzheimer’s disease (AD), amyloid accumulates in highly‐functionally connected brain regions. This selective vulnerability is related to the high neuronal fluctuations, typical of these regions. Dynamic functional connectivity (FC) was introduced to investigate network organization over time, with high network variations indicating regional flexibility, hence promoting functional integration. The relation of early amyloid deposition with FC dynamics remains unclear. Eigenvector centrality (EC) evaluates a node's importance in functional networks, both for the whole functional MRI time series (“static” EC) or within sliding‐windows (“dynamic” EC). We studied the association of cerebrospinal fluid (CSF) amyloid load with static and dynamic EC in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort.

Method

Data for 701 non‐demented participants were available. CSF Aβ1‐42 levels <1000 pg/mL were defined as amyloid positive (A+) (Elecsys assay). Both static and dynamic voxel‐wise EC were computed from rs‐fMRI time series. Static EC differences between A+ and A‐ participants were assessed using linear models. Standard deviation and range of dynamic EC were compared between A+ and A‐ participants within significant clusters of static EC differences, and within 10 resting‐state networks (RSN). Linear models were used to determine interaction between amyloid and cognitive performance on dynamic EC variability (Figure 1).

Result

Demographics and clinical characteristics are shown in Table 1. A+ participants showed lower static EC values in parietal and occipital clusters, and higher static EC values in a medio‐frontal cluster (Figure 2). The medio‐frontal cluster had also lower dynamic EC variability in A+ (Figure 3). The default mode (Figure 4) and the visual networks of A+ participants also showed lower dynamic EC variability (p < 0.001). Dynamic properties in the DMN and visual networks were differentially associated with cognitive domains in the A‐ and A+ groups, with lower variability found in A+ participants with higher cognitive scores (Figure 5).

Conclusion

We demonstrate that early amyloid deposition affects static and dynamic EC, possibly by reducing involvement of functional hubs in different network dynamics and functional integration, thus relating to cognitive dysfunctions. Our data suggest dynamic EC as an early biomarker of the interplay between early amyloid deposition and cognitive decline.
Volumetry of the Olfactory‐Related Structure as a New Biomarker of Individuals at Risk of Alzheimer Disease? Results From the CIMA‐Q Cohort
Authors: Jobin Benoît , Frasnelli Johannes , Boller Benjamin , Group CIMA‐Q
Published: December 2022

Background

Hippocampal and entorhinal atrophies are used as gold‐standard biomarkers of the prodromal stage of Alzheimer's disease (AD). These atrophies are related to episodic memory deficits found in individuals with mild cognitive impairment (MCI). Olfactory deficits have been identified as clinical biomarkers of AD and found in individuals with MCI. Olfactory‐related structures such as the primary olfactory cortex (POC) were found to be atrophied in patients with AD. The aim of this study was to evaluate if the atrophy of hippocampal and entorhinal regions in individuals with MCI was accompanied with the atrophy of the POC regions.

Method

Using voxel‐based morphometry (VBM), we compared hippocampal, entorhinal and POC’s grey matter volume between a group of 93 participants with memory complaint (mean age: 72.15, SD: 4.74) and a group of 40 patients with MCI (mean age: 72.08, SD: 5.51) from the Consortium for the early identification of Alzheimer's disease–Quebec (CIMA‐Q). VBM analyses were done using the region of interest (ROI) approach with a specific mask combining masks for the hippocampus and the entorhinal cortex from the Neuromorphometrics atlas and a mask for POC structures from Northwestern University (Zhou et al., 2019).

Result

VBM analysis reveals smaller bilateral grey matter volume within bilateral hippocampus (left peak: MNI ‐32 −10 ‐22, k = 24, T = 3.78, pFWE corr. = 0.033) (right peak: MNI 30 −8 ‐26, k = 111, T = 4.11, pFWE corr. = 0.016) and right POC (peak: MNI 27 0 ‐14, kE = 20, T = 3.71, pFWE corr. = 0.035) in MCI patients compared to the older participants with memory complaints.

Conclusion

The neurodegeneration of olfactory‐related structures seems to occur in the prodromal stage of AD and atrophy of these structures might represent a way to improve the specificity of preclinical AD if combined with hippocampal atrophy.
The Cognitive Connectome in SCD
Authors: Gonzalez‐Burgos Lissett , Cedres Nira , Garcia‐Cabello Eloy , Diaz‐Galvan Patricia , Westman Eric , Ferreira Daniel , Barroso Jose
Published: December 2022

Background

Subjective cognitive decline (SCD) in cognitively normal individuals is a relevant predictor of future cognitive decline, dementia, and neurodegeneration. Previous studies showed that the cognitive decline cannot be captured by objective neuropsychological testing in SCD. However, whether sophisticated multivariate approaches such as graph theory can potentially capture subtle cognitive abnormalities in SCD individuals is unknown. This study aimed to assess the cognitive connectome in a relatively large cohort of SCD individuals, in comparison with healthy controls (HC), and assess whether such a connectome differs in SCD across age groups.

Method

We included a total of 390 individuals, of which 211 fulfilled the core SCD criteria proposed by the international SCD Initiative (SCD‐I), and 179 individuals were classified as healthy controls. Participants were stratified into early middle‐age (37–50 years, n = 125), late‐middle‐age (51–64 years, n = 119), and elderly (65–78 years, n = 146) groups. We built cognitive networks from 47 cognitive variables separately for each age and study group using graph theory and compared the groups using global measures of average strength, average global efficiency, average local efficiency, and transitivity.

Result

SCD individuals had more segregated networks in all age groups, but more prominently in the late‐middle‐age group. We observed lower within‐module connectivity in SCD individuals, in verbal memory and executive—premotor functions compared with HC. The late middle‐age SCD group showed a pattern of connectivity similar to the elderly HC group. The late‐middle‐age SCD group also showed reduced transitivity compared with the HC. We did not observe significant differences in the rest of the graph measures and in the other groups.

Conclusion

Using a sophisticated multivariate approach, we demonstrate that a segregated pattern of cognitive connectivity seems to underlie SCD, particularly in individuals in the age range 51 to 64 years. After the age of 65 years, this pattern tends to be less segregated, contrary to an efficient dedifferentiation process in aging. This, together with subtle signs of brain pathology and other risk factors identified in SCD may increase the likelihood of future cognitive impairment and dementia.
Using semi‐structured interview to develop a tailored psychological intervention for individuals at risk for familial Frontotemporal dementia
Authors: Greaves Caroline V , Fearn Caroline , Stott Joshua , Rohrer Jonathan D.
Published: December 2022

Background

Frontotemporal dementia is genetic in around a third of cases. Issues such as high penetrance, heterogenous symptoms and unpredictable onset may cause significant challenges for those at‐risk. Few studies have evaluated this experience and no interventions have been designed to support this group. Therefore, investigation of the at‐risk experience is required to ensure an intervention that is tailored to and appropriate for the target population, as outlined in stage 0 of the NIH stage model for Behavioural Intervention Development.

Method

Participants were individuals enrolled in UK GENFI, at‐risk of MAPT, GRN and C9orf72 mutations. Participants included those with unknown genetic status, asymptomatic mutation carriers and non‐carriers. 71 participants completed questionnaires, including GAD‐7 and PHQ‐9 measures, and the Genetic Psychosocial Risk Instrument. 16 qualitative interviews were conducted, regarding feelings experienced throughout the at‐risk journey, support needs and the genetic testing experience. An inductive approach to thematic analysis was used. Themes were then utilised to form the content of the intervention and guide design.

Result

There were no significant differences between genetic groups on GAD‐7, PHQ‐9 and GPRI measures, however 52% participants met the GPRI threshold for referral for psychosocial intervention.

Key themes included: 1) Emotions experienced, 2) How risk influences how you live your life, 3) Coping, 4) Support wanted, 5) Barriers and facilitators, and 6) The importance of understanding the specific difficulties. Many participants expressed a desire for tailored psychological support facilitated by “someone who understands”.

Intervention design

The intervention applies principles largely derived from the Acceptance and Commitment Therapy model and has a blended design comprising of online sessions over eight weeks, with psychoeducational videos and three face‐to‐face sessions. There are seven to ten modules depending on the individual’s genetic status including: anxiety and low mood, rumination, survivor guilt, concern about symptom onset and uncertainty. A pilot study is currently underway and will be completed by April 2022.

Conclusion

Living at‐risk of familial FTD is challenging, often requiring additional support therefore this work demonstrates the importance of NIH stage 0 research in intervention development. Future research should further explore the effectiveness of tailored interventions in at‐risk familial FTD.