bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic accuracy of cognitive assessment in diverse older adults: effects of normative sample and demographic adjustments
Authors: Tsoy Elena , Corrada María M. M. , Deters Kacie D , Medina Luis Daniel , Pa Judy , Tommet Douglas , Vila‐Castelar Clara , Whitmer Rachel A. , Gilsanz Paola , Mungas Dan M.
Published: December 2023

Background

Racial and ethnic disparities in ADRD diagnosis are well documented but remain poorly understood. Clinical ADRD diagnosis relies on neuropsychological assessment, which is interpreted by comparing individual performance to demographically adjusted reference group norms. Differential use of demographic adjustment procedures and sources of normative data may compromise diagnostic accuracy of neuropsychological findings in diverse individuals. Using two different demographic adjustment approaches derived from two distinct normative samples, we generated cognitive impairment categories and evaluated their associations with longitudinal trajectories of independent executive functioning and memory scores.

Method

Participants were 717 older adults (age: 77.5±6.9, 56% women) enrolled in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study who completed up to 3 annual visits. The main predictor was cognitive impairment category (no impairment, single‐domain, multiple‐domain) based on Uniform Data Set Neuropsychological Battery (UDSNB) scores at baseline. UDSNB scores were either demographically unadjusted or adjusted (age, sex, education, and race/ethnicity) using data from the National Alzheimer’s Coordinating Center (NACC; N = 8313, 16% Black, 84% White) or KHANDLE (N = 397, 26% Asian, 18% Black, 30% LatinX, 26% White) samples. Linear mixed effect models were used to examine the associations between differentially derived cognitive impairment categories with longitudinal changes on episodic memory and executive functioning composites from an independent cognitive battery (Spanish and English Neuropsychological Assessment Scales, SENAS).

Result

Cognitive impairment categories derived from the KHANDLE sample were more strongly associated in all four racial and ethnic groups with longitudinal decline on episodic memory compared to the NACC sample‐derived categories (Figure 1). Similar, albeit attenuated, effects were observed in relation to longitudinal decline on the executive function composite. There were no clear differences in the associations between cognitive impairment categories with executive functioning or memory decline using demographically adjusted vs. unadjusted scores.

Conclusion

Our results highlight the need for greater representation of diverse individuals in normative samples underlining the limitations of the NACC‐derived normative algorithms for cognitive assessment of individuals from diverse populations. Further investigations into the clinical value of the practice of demographic adjustments are also warranted.
Effects of Mutations in Tau’s Proline Rich Region on Epileptic Activity and Sleep in Mouse Models of Epilepsy
Authors: Vicente Mariane Cristine , Vaknalli Rahil , Anderson Ashley J. , Stepter Joshua S , Onanyan Nane , Narasani Anushka , Ravishankar Sahana , Western Ava W , Thayer Stanley , Vossel Keith , Vaknalli Rahil
Published: December 2023

Background

Genetic ablation of tau prevents seizures, memory loss, and premature mortality in transgenic mouse models of Alzheimer’s disease, but the exact mechanisms are unknown. We tested the hypothesis that variants in tau’s proline rich domain, which affect binding to SH3‐containing proteins, prevent epileptic activity in epilepsy models.

Method

We used the following lines: 1) AxxA6 (P‐to‐A substitutions in 6th PxxP motif in tau) and 2) R221A: R‐to‐A substitution at amino acid corresponding to 221 in human 2N4R tau. Tau knockout mice were used as a benchmark. We injected kainic acid (25 mg/kg, ip), and analyzed latency to different seizure severity levels (SSL) over 3 hours: 1 to grade 8. We also crossed AxxA6 and R221A mice with the Kv1.1 knockout (Kcna1–/–) model of epilepsy and performed 24‐hour epidural video‐electroencephalography and electromyography in mice ages 5‐8 weeks. We used ex vivo slice electrophysiology and measured burst frequency in CA3 after bath‐applied picrotoxin and 4‐amino‐pyridine.

Result

Tau knockout mice exhibited higher latency to seizure stages than wildtype mice (WT) after kainic acid injections (p<0.05, One‐way ANOVA), consistent with previous studies. Heterozygous AxxA6 mice showed reduced susceptibility to seizures (n = 4‐6 per genotype; SSL 4‐8: ∼ 9.5 vs WT: 4.5 seconds, p<0.05, One‐Way ANOVA). The heterozygous R221A tau variant decreased mortality in Kcna1 KO mice (p<0.05). Epileptic spikes in Kcna1 KO mice averaged 22 spikes/hour (AxxA6 n = 4, R221A n = 7), and AxxA6 (homozygous and heterozygous) tau variants decreased epileptic activity to ∼2 spikes/hour (p<0.05, One‐Way ANOVA, excluding statistical outliers) in Kcna1 KO mice. Kcna1 KO mice showed a higher percentage in the awake state during light and dark phases compared to WT mice (n = 5, p<0.05, t‐test). The AxxA6 and R221A tau variants did not alter sleep‐wake cycle in Kcna1 KO mice. Kcna1 KO mice showed increase burst frequency in CA3, and heterozygous and homozygous R221A tau variants reduced bursting frequency (p<0.05, One‐Way ANOVA).

Conclusion

The AxxA6 and R221A tau lines show partial reduction in seizure susceptibility in models of epilepsy compared to the tau knockout line. The tau protein variants do not affect regulation of the sleep‐wake cycle in the Kcna1 model.
The international network of scholars of the US‐based Living Alone with Cognitive Impairment Project: advantages, methods, and lessons learned
Authors: Portacolone Elena
Published: December 2023

Background

Establishing international networks allows researchers of Alzheimer’s disease and related dementias (ADRD) to draw lessons from foreign best practices in terms of policies, programs, interventions, and study design, thus broadening perspectives. A broad perspective is essential to design studies efficiently. Furthermore, international comparisons spurred by international networks can point to the advantages oand shortcoming of national policies and programs. Despite the importance of developing international networks and collaborations, researchers often do not leverage the opportunity to develop international research networks of scholars with comparable research interests. This session will draw from the expertise gained by the research team of the 5‐year US‐based Living Alone with Cognitive Impairment Project to develop and establish an international advisory group advising on the design of their mixed‐method study.

Method

In the first year of the 5‐year project (2021) we convened an International Advisory Group and then 4 plenary meetings with its 15 members which include scholars from all continents, plus an officer of the World Health Organization.

Result

Regular interactions between the research team and the International Advisory Group led to: 1) systematic review of the international literature on services available to older adults living alone with cognitive impairment; 2) a seminar series of work‐in‐progress seminars; 2) a grant submission to fund an international conference; 3) enhanced design of the US‐based project (e.g., unplanned new research questions).

Conclusion

The oversight, and regular engagement, of an International Advisory Group has allowed the Living Alone with Cognitive Impairment Project to better understand the advantages and shortcoming of US‐policies and programs to support older adults living alone with cognitive impairment. The practice of establishing an international advisory group can be easily replicated by researchers in studies supporting underserved populations with cognitive impairment.
Statin therapy reduces the risk of AD: Clinic to bench translation for protective mechanism
Authors: Torrandell‐Haro Georgina , Chen Shuhua , Brinton Roberta Diaz
Published: December 2023

Background

Cholesterol dysregulation is a well‐documented factor involved in the pathophysiology of Alzheimer’s Disease (AD). APOE4, which is involved in cholesterol transport, is recognized as the strongest genetic risk factor for late‐onset AD. In a previous study using clinical data, we showed that exposure to statins, a first‐line cholesterol lowering therapeutic, was associated with a reduced risk of developing AD. Another study showed the risk reduction associated with statins was greater in APOE4 carriers. Although the effects of statins in the periphery are well documented, the mechanisms by which statins act in the brain remain poorly understood.

Method

This study aimed to identify potential mechanisms by which statins impact AD pathology at a cellular level and the different response by APOE genotype. Humanized APP/APOE3 and APOE4 mouse neurons and astrocytes were co‐cultured and treated with vehicle or atorvastatin at clinically relevant concentrations. Metabolic flux analysis was used to determine the impact of statins on mitochondrial bioenergetics and dynamics. Multi‐electrode array (MEA) was used to conduct electrophysiological recordings on hippocampal neurons. Lipid droplet burden in astrocytic cells was determined using LipidTOX staining and confocal microscopy. qPCR and Western Blot were used to determine the expression of key proteins involved in cholesterol transport.

Result

In this study, hippocampal neurons treated with atorvastatin in the presence of astrocytic cells induced a significant increase in the number of spikes and spike frequency, as well as the number of bursts and number of spikes within a burst. In contrast, in the absence of astrocytes atorvastatin exposure in neurons did not exhibit a significant difference compared to vehicle. Electrophysiological properties were increased in a dose‐dependent manner and the effect was greater 24‐hours following treatment. Atorvastatin also increased astrocyte mitochondrial respiration whereas it did not in neurons or in neurons co‐cultured with astrocytes.

Conclusion

Outcomes of these analyses indicated that atorvastatin acts primarily on astrocytes. Specifically, atorvastatin increased mitochondrial respiration in astrocytes and increased synaptic activity on neurons which was astrocyte dependent. These results provide evidence of a neuroprotective role of atorvastatin by regulating lipid metabolism deficits in a cell‐specific manner.

Acknowledgments: NIA P01AG026572 and R01AG057931 to RDB.
Computational identification of precision therapeutics for Alzheimer’s disease specific to endocrine and APOE genotype status
Authors: Vitali Francesca , Zhang Jessica , Wang Tian , Brinton Roberta Diaz
Published: December 2023

Background

Alzheimer’s disease (AD) affects 6.5 million people in the US, two‐thirds of which are women. Despite extensive research, there are currently no highly effective treatments for AD. The greatest risk factors for AD are age, chromosomal female sex and APOEε4 genotype. A key driver of chronological and endocrinological aging is the activation of innate and adaptive immune systems occurring in midlife female brain. To effectively prevent and treat AD, it is crucial to develop computational methods that take into account these factors and screen for personalized therapeutics.

Method

RNAseq data of 15‐month acyclic vs 9‐month regular APOEε3/ε3 and APOEε4/ε4 female mouse models were analyzed to identify APOE‐specific Differentially Expressed Genes (DEGs, pvalue<.01). STRING Protein‐Protein Interaction (PPI) database was used to extract protein interactors for the two APOEε3/ε3 and APOEε4/ε4 DEG lists and construct two APOE‐specific AD PPI networks. Target Proteins (TPs) candidates in each network were identified using the DrugBank database by selecting only proteins targeted by at least one FDA‐approved drug. A score of drug synergy was developed to rank FDA‐approved drugs based on the number of target proteins in‐ vs out‐ of the APOE‐AD specific networks and their distance to DEG nodes.

Result

From RNAseq analyses, we identified a total of 265 DEGs for APOEε3/ε3 and 452 DEGs for APOEε4/ε4 genotype. The APOE‐AD‐specific PPI networks resulted in 1,711 nodes (proteins) and 21,445 edges (PPIs) for the APOEε3/ε3 genotype and 2,841 nodes and 35,493 edges for APOEε4/ε4 genotype. Using the DrugBank database, 342 and 568 potential therapeutic targets were identified in the APOEε3/ε3 and APOEε4/ε4 networks, respectively. Finally, drug synergy score enabled ranking 99 therapeutics for APOEε3/ε3 network and 102 drugs for APOEε4/ε4 network, of which 19 resulted in both lists.

Conclusion

This study presents a network‐based approach for identifying personalized therapeutics for AD based on endocrine transition changes and APOE genotype. The results suggest that there is greater transcriptomic dysregulation in female APOEε4/ε4 brains compared to APOEε3/ε3 brains. The proposed computational approach has the potential to advance precision medicine for the prevention and treatment of AD, and future research will focus on identifying the most effective combinations of therapeutics.
One scale, different apathy? Specific neuroanatomical substrates of apathy in dementia
Authors: Mariano Luciano Inácio , Oliveira Maciel Thiago , Caramelli Paulo , Souza Leonardo Cruz
Published: December 2023

Background

Apathy is a multidimensional neuropsychiatric feature that affect behaviour, cognition, and emotional reaction. Hence exploring its neuroanatomic substrates offers the possibility of understanding the variability of this symptom.

Method

20 Healthy Controls (HC), 19 patients with AD and 20 patients with bvFTD, matched for age, sex, education, and time of disease were included. Participants underwent a full clinical and neuropsychological assessment and a 3T MRI acquisition. Neuroimaging was processed in the FreeSurfer software, and cortical thickness (CTh) was obtained for 68 cortical regions (34 per hemisphere) for each participant. An index was calculated by dividing the raw volume for the intracranial total volume (ITV) to account for individual variability. This index was then correlated with each group’s Starkstein Apathy Score (SAS). A linear regression model controlled for general cognition, executive function, memory function, and social cognition function.

Result

AD and bvFTD had a worse cognitive performance, with bvFTD presenting a slightly more dysexecutive profile than AD. The regression model showed that the apathy in AD is associated with the CTh of the Left Entorhinal cortex (F(1,31) = 5,165; p = 0.030; R2 = 0.527). For bvFTD, the regression model found that SAS correlated with the Right Lateral Orbitofrontal cortex (F(1,30) = 5.69319; p = .009; R2 = .804); the Right Rostral Anterior Cingulate (F(1,29) = 4.95855; p = .003; R2 = .856); the Left Lateral Orbitofrontal (F(1,28) = 4.67979; p = .042; R2 = .877); the Left Precentral cortex (F(1,27) = 4.34826; p = .027; R2 = .897); and the Left Postcentral cortex (F1,26) = 3.98166; p = .019; R2 = .917).

Conclusions

Our results show that apathy is associated with specific cortical regions according to each disorder. For AD, apathy is related to the entorhinal cortex, even when controlling for mnemonic performance. In contrast to the single cortical region found in AD, bvFTD had several, indicating how more complex it is in the condition and possibly explaining why apathy is harder on bvFTD than AD. Generally, regions associated with apathy in bvFTD relate to social cognition, inhibitory control, behavioural activation and somatosensorial processing. The different pattern of cortical regions associated with apathy maps how plural apathy is and the need to consider its differences for each disease.
Indigenous individuals present distinct modifiable risk factors of dementia than white individuals: an ELSI‐Brazil study
Authors: Formoso Carolina Rodrigues , Borelli Wyllians Vendramini , Rosa‐Neto Pedro , Ferreira Pamela C.L. , Pascoal Tharick A. , Castilhos Raphael Machado , Zimmer Eduardo R
Published: December 2023

Background

Risk factors for dementia have distinct frequency and impact according to racial origins. Our aim was to identify differences of modifiable risk factors of dementia related to Indigenous and White individuals, estimate their Population Attributable Fraction (PAF) and highlight the differences between races.

Methods

An epidemiological cohort named ELSI‐Brazil was used to estimate the prevalence of 10 modifiable risk factors for dementia among 2 races ‐ White and Indigenous. he ELSI‐Brazil cohort consists of 9412 individuals (63.55+‐10.14 years of age). This cohort comprises individuals at/ or above 50 years of age from across the country. Complex sampling warrants nationwide representativity for diseases with low prevalence. Races were self‐reported according to the Brazilian Census. Sample weighting was used to estimate the prevalence and PAF of each risk factor in each race.

Results

Among 3810 individuals included, 220 were Indigenous individuals. The Indigenous were younger (mean age 62.6 [±9.6] years) and less educated (mean 4.3 [±4.0] years) than the White (mean age 64 years [±10.2], mean education years 6.2 [±4.4]). Both were composed by most females. The most important weighted PAF were hearing loss for both races (Indigenous 16.7%; White 15.2%). The most prevalent risk factor for both were less education, which were higher in Indigenous individuals (69.5%) than in White individuals (55.1%). By contrast, social isolation was less prevalent in Indigenous (1.5%) than White (5.1%). Overall adjusted PAF was lower in Indigneous (38.9%), compared to White (49,2%).

Conclusion

White and Indigenous presented different prevalence of risk factors, though they had hearing loss as the most impacting risk factor for dementia. However, it seemed that Ocidental risk factors didn’t produce the same effect in indigenous individuals as in white individuals. Thus, indigenous individuals presented a distinct profile of risk factors of dementia than individuals from other self‐reported races.
Impact of the pandemic time on the mental health of Chilean caregivers: 1‐year follow‐up preliminary results
Authors: Olavarria Loreto , Loyola Walter Sepúlveda , Caramelli Paulo , Barbosa Maira Tonidandel , Andrade Caíssa , Lema Jose , Slachevsky Andrea
Published: December 2023

Background

The worldwide COVID‐19 pandemic has been a major challenge for the health system in the past years. From March 2020 until 2022 there were extensive lockdowns in Latin America to ensure physical distance and reduce virus transmission. Previous studies reported the negative impact of social isolation on people living with dementia, however, the impact on caregivers has been little studied so far. This study analyses the mental impact of the pandemic time on caregivers of people with dementia.

Method

In order to evaluate clinical and behavioral changes from the prior assessment conducted in 2020 with people with dementia and their family caregivers, a 1‐year follow‐up phone study was conducted with the same sample from the previous research. Participants from Chile were assessed by two semi‐structured questionnaires.

Results

106 caregivers of patients with dementia were interviewed during the year 2020 (age: 73.3 ± 9.5 years; female: 57%). After one year of follow‐up, 61 caregivers were contacted. Compared to baseline, after one year of follow‐up, 75% % of the caregivers reported worse physical and mental health (p:0.028), 56% more sadness associated with patient care (p:0.001); 93% reduced sleeping time (p:0.07) and 51% received more help to care the patient with dementia (p:0.036). Results are reported in table 1.

Conclusion

Although the caregiver had more daily assistance in 2021 compared with 2020, the pandemic time had a negative impact on their physical and psychological health. Even if these results might be explained by the normal evolution of dementia, the follow‐up results did not show a significant behavioral change in the person with dementia, and so the changes in the caregiver might be more a consequence of the pandemic rather than exclusively the disease.
Arterial spin‐labeling spatial coefficient of variation is associated with cerebral small vessel disease
Authors: Robb W Hudson , Kim Darcie S , Houston Michelle L , Pechman Kimberly R. , Verde Audrey R. , Davis L. Taylor , Landman Bennett A. , Hohman Timothy J. , Jefferson Angela L.
Published: December 2023

Background

Cerebral small vessel disease (SVD) is the most common pathology to co‐occur with Alzheimer’s disease but pathophysiologic mechanisms leading to SVD are poorly understood. The arterial spin‐labeling (ASL) spatial coefficient of variation (sCoV), a proxy marker of arterial transit time (ATT), may better reflect SVD‐related hemodynamic disturbances than ASL‐derived cerebral blood flow (CBF). We investigated whether grey matter CBF and grey matter sCoV each related to neuroimaging markers of SVD, including white matter hyperintensities (WMHs), basal ganglia enlarged perivascular spaces (ePVS), cerebral microbleeds (CMBs), and lacunes.

Methods

Vanderbilt Memory and Aging Project participants free of clinical dementia and stroke at study entry (n = 312, 73±7 years, 39% mild cognitive impairment, 41% female) underwent multimodal 3T brain magnetic resonance imaging to quantify ASL parameters and SVD burden. Pseudo‐continuous ASL assessed CBF in total grey matter. Grey matter sCoV was calculated as σ(CBFGrey Matter)/μ(CBFGrey Matter). WMHs and ePVS volumes were quantified using automated methods and ePVS volumes were standardized to basal ganglia volume. CMBs and lacune counts were quantified by an expert rater. Ordinary least squares regression models cross‐sectionally related grey matter CBF and sCoV individually to log‐transformed burden of each SVD marker. Models were adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), intracranial volume, grey matter volume, and apolipoprotein E‐ε4 status.

Results

Grey matter CBF was unrelated to all SVD outcomes (p‐values>0.25). Higher grey matter sCoV was associated with greater WMHs (β = 2.1, p = 0.001), ePVS (β = 0.004, p = 0.0003), and lacunar infarcts (β = 1.4, p = 0.0006) but not CMBs (β = 1.0, p = 0.06).

Conclusions

Our findings align with previous results showing that grey matter sCoV is a valuable marker of SVD. In contrast to previous work, we found an association between higher grey matter sCoV and higher basal ganglia ePVS burden. Potentially, our use of volumetric ePVS quantification rather than qualitative ePVS burden increased our ability to detect this association. As sCoV is a proxy marker of ATT, future work should consider quantifying sCoV or ATT in addition to CBF to better characterize SVD‐related hemodynamic disturbances.

Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, P20‐AG068082
Plasma p‐tau181 levels in Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB)
Authors: Hsiung Ging‐Yuek Robin , Kumar Pankaj , Mousavi Ali , Encarnacion Mary , Frykman Hans
Published: December 2023

Background

The fundamental pathological process in AD involves amyloid(Aβ) deposition and Tau hyperphosphorylation (ptau). Plasma ptau has been proven as more accessible and less invasive biomarker than CSF for the assessment of AD pathological features. DLB is another common cause of dementia in the elderly and has overlapping features with AD. Thus, the detection of Alzheimer’s biomarkers might be useful for distinguishing the underlying pathology of AD from other concurrent pathologic processes. In this study, we compared the plasma levels of p‐tau181 in patients with clinically diagnosed DLB and AD.

Method

We examined EDTA plasma samples of patients assessed at the UBC Hospital Clinic for AD. The cohort was clinically characterized as control (n = 89) if no significant cognitive impairment was found, AD (n = 195) if they fulfill the NIA‐AA criteria (McKhann 2011), and DLB (n = 39) if they fulfill the consensus criteria for DLB (McKeith 2005; McKeith 2017). The samples were analyzed by a p‐tau181‐specific Simoa assay.

Result

The mean age of the cohort is 69.2 ± 10.3 with the control 63.4 ± 8.7, AD 70.1 ±9.9 and DLB 77.8 ± 8. There are 74.2% females in the controls, 52.8% in AD, and 35.9% in DLB.).

The patients with DLB were older than the cases of AD and controls (p<0.001) and there was no significant effect of age on plasma ptau‐181 concentrations (p = 0.65). There were more females in the controls and AD groups compared to DLB (p<0.001), however, there was no significant correlation between sex and plasma ptau‐181 (p = 0.24). While the plasma p‐tau181 concentrations of cases with AD (74.1 ± 35.6 pg/ml) were slightly higher than DLB (73.2 ± 44.4 pg/ml), they were not significantly different. However, they were significantly higher than the control group (26.5 ± 23 pg/ml) (p < 0.001).

Conclusion

In current study, plasma p‐tau181 levels did not differentiate the DLB group from the AD, but both groups were significantly higher than controls. This suggests that DLB often have co‐existing AD pathology, making their p‐tau measurements like the AD group. Further studies with autopsy‐defined samples will be needed to clarify the role of plasma p‐tau181 in DLB.
PK/PD analyses of ARIA‐E and isolated ARIA‐H in Lecanemab Clarity AD study
Authors: Cao Youfang , Majid Oneeb , Hussein Ziad , Willis Brian A. , Takenaka Osamu , Penner Natasha , Yasuda Sanae , Reyderman Larisa
Published: December 2023

Background

Clinical efficacy of lecanemab was confirmed in a Phase 3 trial (Clarity AD, NCT03887455), reducing markers of amyloid in early Alzheimer’s disease and slowing cognitive and functional decline as compared to placebo. However, some subjects experienced amyloid‐related imaging abnormalities (ARIA) associated with edema/effusion (ARIA‐E) or hemorrhage (ARIA‐H). PK/PD analyses were performed to explore the potential relationship between ARIA‐E and isolated ARIA‐H incidences with lecanemab exposure and key covariates.

Method

The Clarity AD trial randomized 1795 participants to receive lecanemab (N = 898, 10 mg/kg bi‐weekly) or placebo (N = 897). A total of 177 ARIA‐E incidences were observed from pooled Phase 2 (NCT01767311) and Phase 3 (Clarity AD) data. Additionally, a total of 150 participants from Clarity AD trial experienced treatment‐emergent isolated ARIA‐H (an ARIA‐H event without concurrent ARIA‐E). The ARIA‐E incidence rate was modeled as a function of lecanemab steady state exposures, and effects of potential covariates were explored. Graphical PK/PD analysis was performed to examine the relationship between isolated ARIA‐H and lecanemab steady‐state exposures.

Result

The observed ARIA‐E incidence was best modeled using lecanemab maximum concentration at steady‐state (Css,max) with ApoE4 genotype identified as a significant covariate. The model indicates a higher ARIA‐E incidence in homozygous carriers compared to non‐homozygous carriers or noncarriers (p<0.0001). At mean lecanemab Css,max = 305 µg/ml in subjects receiving 10 mg/kg bi‐weekly in Clarity AD, the model predicted a 5.45% (95% CI: 3.75% ‐ 7.84%) incidence of ARIA‐E in noncarriers, 9.85% (95% CI: 7.96% ‐ 12.1%) in heterozygous, and 28.0% (95% CI: 22.6% ‐ 34.1%) in homozygous carriers. No other covariate explored (age, sex, race, baseline MMSE, or occurrence of anti‐drug antibodies) had a statistically significant effect on ARIA‐E incidence. For isolated ARIA‐H, the graphical analysis identified no apparent relationship between isolated ARIA‐H incidence with lecanemab exposure. Isolated ARIA‐H incidence was associated with ApoE4 genotype, with homozygous having the highest isolated ARIA‐H incidence.

Conclusion

The incidence of ARIA‐E increased with lecanemab Css,max. The incidence rate of isolated ARIA‐H was demonstrated independent of lecanemab exposure. The ApoE4 genotype impacts both ARIA‐E and isolated ARIA‐H, with increased incidences in homozygous carriers compared to heterozygous carriers or non‐carriers.
Neuronal populations in the inferior temporal gyrus with truncated tau inclusions occur as early as those with hyperphosphorylated tau inclusions in Alzheimer’s disease, however they do not completely overlap
Authors: Oh Ian Michael
Published: December 2023

Background

Alzheimer’s disease (AD) features stereotypical spread of hyperphosphorylated tau (p‐tau) and beta‐amyloid. Although other pathological tau posttranslational modifications (PTMs) have been described in AD, a prevalent disease model preconizes that other tau PTMs always overlap with p‐tau, making the latter an excellent marker of tau pathology burden. We recently showed in experimental studies that truncated tau (tr‐tau), a pathological tau PTM generated via cleavage by active caspases, is as common as p‐tau in neurons at late AD stages; however, only about 40% of tr‐tau positive neurons also show p‐tau positivity. This makes tr‐tau a potential marker of AD previously invisible at neuropathological investigation or a potential target of diagnostic tool development. We sought to determine how early in AD tr‐tau is detected compared to p‐tau and to what degree tr‐tau and p‐tau neuronal populations overlap at early AD stages.

Methods

We used multiplex immunofluorescence to probe tr‐tau (D13, D402, D418, TauC3) and p‐tau (PHF1) species in the same tissue slides of postmortem human brain tissue of healthy controls and subjects at progressive AD stages. We quantified neuronal tau pathology and colocalization in digital images of inferior temporal gyrus (ITG) as representative of an area involved in p‐tau pathology in intermediate stages.

Results

Our preliminary analysis included 14 cases (4 controls, 10 AD) from all Braak stages (1:1:2:3:3:2:2 for Braak 0 through 6). Of the cases used in the study, 71% were male and the mean (SD) age of death was 82.3 (10.9). As expected, p‐tau was detected from Braak 4; however, we detected tr‐tau species from Braak 3 (Fig. 1). Both p‐tau and tr‐tau burden increased with Braak stage (Fig. 2). The overlap between tr‐tau and p‐tau positive neuron populations was 30.8% at Braak 4 (Fig. 3A) and increased to 54.6% at Braak 6 (Fig. 3B).

Conclusion

Neuronal tr‐tau deposits develop in AD as early as p‐tau pathology. Even in earlier stages, the % of overlapping is moderate. This corroborates tr‐tau as a potential biomarker of tau pathology in AD not covered by p‐tau screening. We are currently finalizing analysis of a much larger cohort including other brain regions.
Signatures of resolution reprogramming in amyloid‐challenged microglia
Authors: Hamlett Eric D , Kondrikova Galina
Published: December 2023

Background

Specialized pro‐resolving mediators (SPMs) promote inflammatory resolution and homeostasis and are thought to have specific reprogramming effects on innate immune cells like monocytes and microglia. Decreased SPM levels have been correlated with chronic neuroinflammation, late‐stage Alzheimer’s disease (AD) and neuropathology in humans, yet few studies have explored the signatures of

Method

The Ts65Dn mouse develops amyloid hyperexpression, neuroinflammation and neurodegeneration. We administered the SPM, Resolvin E1 (RvE1), for 1 month to control and Ts65Dn mice and measured memory using a series of tasks. We quantified resolution signaling responses using standard immunoblot. We measured microglial activation using immunofluorescence and cell characterization software. We then challenged Human innate immune cell culture models (monocytes and microglia) with amyloid‐beta and tau oligomer activation and/or administered RvE1 to promote resolution. We will employ RNASeq to learn how RvE1 resolution reprogramming affects transcriptional outcomes in these cell culture models.

Result

RvE1 significantly reduced microglial activation and cytokine expression in the Ts65Dn mice, suggesting broad effects on central and peripheral innate immunity. We discovered that chronic RvE1 leads to compensatory response in specific G protein coupled receptors within the resolution family and in the PPAR‐gamma receptor and to specific signaling events. We are quantifying transcriptional outcomes to better define the nuclear program that underlies resolution.

Conclusion

We have demonstrated that RvE1 modulates inflammation in a mouse model. Understanding the molecular signatures of resolution reprogramming in cells will be key to identifying prognostic indicators and molecular mechanisms.
Neuronal stimulation‐regulated RNA splicing defects in tauopathies are corrected by treatment with a p75 NTR modulator
Authors: Latif‐Hernandez Amira , Moran‐Losada Patricia , Yang Tao , White Halle , Tran Kevin C , Liu Harry , Massa Stephen M. , Wyss‐Coray Tony , Longo Frank M.
Published: December 2023

Background

Long‐term maintenance of synaptic adaptations, assessed by long‐term potentiation (LTP), relies on gene induction, and can be impaired by pathological forms of tau protein in Alzheimer’s disease and related dementias (ADRD). We have previously shown that alterations in activity‐dependent gene expression profiles present in tauopathy mice are normalized by LM11A‐31 (C31), a small molecule p75 neurotrophin receptor (NTR) signaling modulator. However, altered gene expression levels represent only part of the complexity of the activity‐regulated transcriptional program. Since neuronal stimulation regulates alternative splicing of a number of activity‐regulated transcripts, and its disruption is associated with dysfunctional changes in ADRD, we aim to identify potential alternative splicing events related to tau‐mediated synaptic dysfunction and whether such alterations are influenced by treatment with a p75 NTR modulator.

Method

PS19 (P301S) and wildtype mice were treated with vehicle (Veh) or C31 by oral gavage at 6 months of age for 3 consecutive months. Gene translation‐ and protein synthesis‐dependent synaptic plasticity was induced by applying three events of theta burst stimulation (TBS). RNA sequencing on stimulated [(+) TBS] slices was used to generate activity‐related profiles of alternative splicing events at the isoform level.

Result

We identified axon guidance, glutamatergic synapse, long‐term potentiation and calcium signaling KEGG pathways among the top significant pathways with isoforms down‐regulated in (+) TBS PS19 relative to (+) WT slices. This isoform downregulation was substantially mitigated in (+) TBS slices from PS19 mice treated with C31 (see figure). For example, CACNA1H‐202, a splice‐variant that encodes a voltage‐gated calcium channel protein required for proper synaptic function, is found among the splice variants down‐regulated in Veh and up‐regulated in C31‐treated (+) TBS PS19 slices. Conversely, Prickle2‐204 isoform, associated with the formation of glutamatergic synapses, is up‐regulated in Veh and down‐regulated in C31‐treated (+) TBS PS19 slices. Currently, we are validating and examining the roles of these key C31‐modulated isoforms in neuronal function and synaptic strength as candidate molecular mechanisms involved in activity‐related effects contributing to tau‐induced neurodegeneration.

Conclusion

We identified neuronal activity‐related mRNA isoform modulation by C31, indicating that p75NTR signaling might influence alternative splicing events that compromise synapse function in ADRD.
PARTIAL VOLUME CORRECTION TECHNIQUES FOR LONGITUDINAL TAU‐PET QUANTIFICATION: A COMPARISON STUDY
Authors: Costoya‐Sánchez Alejandro , Moscoso Alexis
Published: December 2023

Background

The selection of an appropriate Partial Volume Correction (PVC) is crucial for evaluating tau accumulation rates using 18F‐Flortaucipir (18F‐FTP). PVC can reduce the impact of off‐target binding, but it can also increase noise and variability. While these effects may be averaged on cross‐sectional studies, they might be of paramount importance when evaluating within‐subject longitudinal tau‐PET signal. The aim of this study is to evaluate the robustness of different PVCs for the evaluation of tau accumulation rates in longitudinal 18F‐FTP studies, as measured by their correlation with cognitive clinical progression.

Method

111 cognitively impaired subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with serial 18F‐FTP PET and T1 images, as well as cognitive performance evaluation available for a 2‐year follow‐up period, were included in the study. 18F‐FTP PET images were corrected by applying a traditional deconvolution PVC (Grey matter only), the reblurred Van‐Cittert (RVC) analytical PVC (grey + white matter), and 2 voxel‐based PVCs, the region‐based voxel‐wise correction (RBV) and the iterative Yang (iY). Longitudinal rates of change for the regional standard uptake value ratios (SUVR) of the temporal meta‐ROI were computed for the images corrected for the different PVCs, and their correlation with the rates of change of the ADAS‐Cog 11 cognitive performance metric was analyzed.

Result

The deconvolution PVC correction showed the strongest correlation between decreased cognitive performance and increased tau accumulation rates (p<0.001, ρ = 0.38), followed closely by the RBV (p<0.001, ρ = 0.36) and iY (p<0.001, ρ = 0.35) corrections (Fig. 1). In contrast, the RVC results (p = 0.03, ρ = 0.20) were comparable to not applying any PVC at all (p = 0.03, ρ = 0.21).

Conclusion

Our findings suggest that longitudinal FTP studies might benefit from the use of PVC techniques for the evaluation of tau accumulation rates. Tau uptake rates of change tracked the observed clinical progression more accurately after certain PVC corrections were applied. Moreover, a simple deconvolution PVC has been shown to perform similarly to more complex, voxel‐wise corrections such as the RBV and iY.
Combined effect of prebiotic and probiotic strains restores cognitive impairment via attenuating synaptosis in the hippocampus of mice fed with high fat diet and streptozotocin diabetes‐induced dementia
Authors: Obisesan Abiola Oluwatosin , Olaitan Olanrewaju Mojisola , Omosebiola Jesutosimi Oyindamola , Akawa Oluwole Abidemi , Olayinka Juliet Nnenda
Published: December 2023

Background

Dementia is known as neurodegenerative disease which causes decline in the cognitive domains of memory and thinking, leading to memory loss of an individual especially the aged. Diabetes mellitus causes brain structure changes and cognitive decline, and it has been estimated that diabetes doubles the risk for dementia. Probiotics combined with prebiotics on the other hand, seem to have a positive effect and reverse memory loss

Method

This study employed ninety (90) male bulb/c albino mice weighing between 25 and 28 grams (n = 15). Animals were housed in plastic cages at room temperature under good hygienic conditions, had free access to animal pellets and water ad libitum. Mice were fed with a high fat diet to imitate obesity after which Diabetes was induced by one administration of STZ (50 mg/kg, IP) freshly dissolved in citrate buffer following an overnight fasting on 22nd day. Probiotic strains and Prebiotics were administered with prepared suspension containing 107 and 109 CFU/ml of probiotics and prebiotics (3mg and 5 mg) body weight orally for pretreatment and posttreatment after streptozotocin induction.

Result

Results from this study shown that there was a significant decrease in glucose levels of animals treated with probiotics and prebiotics combined supplementation in both pretreatment (HFDS +109 CFU/ml + 5 mg) and post‐treatment group (HFDS +109 CFU/ml + 5 mg) with insulin resistance. AChE levels significantly reduced at the combined probiotics and prebiotics pretreatment (HFDS +109 CFU/ml + 5 mg) and post‐treatment group (HFDS +109 CFU/ml + 5 mg). With relation to BDNF gene expression analysis, combined probiotics and prebiotics showed high expression of the BDNF gene in the combined probiotics and prebiotics pretreatment (HFDS +109 CFU/ml + 5 mg) and post‐treatment group (HFDS +109 CFU/ml + 5 mg). Administration of combined probiotics and prebiotics improved memory and learning, insulin resistance, animal weight, glucose levels and BDNF expression.

Conclusion

Combined probiotics and prebiotics demonstrated neuroprotective and anti‐neuroinflammatory activity in the experimental animals and was able to attenuate synaptosis and promote synaptogenesis in diabetic mice which started receiving treatment. The combined supplementation also restores cognitive impairment and memory function.
A hybrid algorithm of machine learning and optimization to identify Super‐Agers using rsfMRI data
Authors: Fili Mohammad , Parvin Mohammadiarvejeh , Hu Guiping , Willette Auriel A
Published: December 2023

Background

Aging and cognitive decline are often associated with each other. However, some adults called Super‐Agers have superior cognitive performance relative to age, with a comparable cognitive performance against healthy middle‐aged individuals. This study employs resting‐state functional Magnetic Resonance Imaging (rsfMRI) and demographic information to distinguish Super‐Agers from Cognitive Decliners.

Method

First, Principal Component Analysis (PCA) is applied to a set of four cognition tests which were recorded for two‐time points, (baseline visit in 2006‐2010) and (follow‐up visit starting in 2014) to create the initial latent cognitive trajectories groups. Then, a hybrid algorithm of machine learning and optimization is developed to predict the latent groups using orthogonal neural networks. The proposed algorithm utilizes Bayesian Optimization to optimize the labeling procedure and a logistic regression model to classify participants.

Result

We compared the performance of the proposed algorithm against two groups of baseline models: 1) four models, each using only one of the cognition tests at a time for labeling; 2) two models, each with a restricted set of features (one using only demographics information, and the other one using rsfMRI data). The proposed algorithm outperformed the baseline models, achieving an AUC of 88% when distinguishing between Super‐Agers and Cognitive Decliners.

Conclusion

The proposed algorithm is capable of distinguishing cognitive trajectories with high success. The combination of demographics and rsfMRI datasets improved the overall performance compared to individual datasets.
Association of Plasma β‐amyloid (Aβ) 42/40 and Incidence of Dementia in Black and White Older Adults
Authors: Jiang Xiaqing , Graff‐Radford Neill R , Younkin Steven G. , Yaffe Kristine
Published: December 2023

Background

Plasma biomarkers such as Aβ 42/40 have emerged as important tools to detect dementia risk, although whether plasma Aβ 42/40 levels and the associations with dementia risk differ by race is unclear. As part of the Health, Aging, and Body Composition study, we compared the plasma levels of Aβ 42/40 ratio and the associations with 15‐year dementia risk by race among community‐dwelling Black and White older adults.

Methods

We studied 997 dementia‐free participants (55% women, 54% Blacks) aged 70‐79 years (mean age 74.5±2.9) enrolled at baseline (1997‐98). We defined incidence dementia over 15 years based on hospital records, prescription for dementia medication, or a decline ≥1.5 standard deviations in the Modified Mini‐Mental State Examination score. Stored plasma obtained one year after baseline was used to measure Aβ with Innogenetics INNO‐BIA assays at Mayo Clinic, Jacksonville, FL. Plasma Aβ42/40 ratio was categorized into low, medium, and high tertiles. We used linear regression to estimate the difference in log‐transformed Aβ42/40 in Black and White participants and back‐transformed the effect estimates. We assess the association between Aβ42/40 (by tertiles) and dementia risk using Cox proportional hazards model stratified by race. All models were adjusted for age, sex, hypertension, diabetes, high cholesterol, and obesity, and we tested for interactions by race.

Results

Black participants had significantly lower Aβ42/40 than White participants (‐4.4%, 95% CI ‐8.1% to ‐0.6%). In stratified analysis, lower Aβ42/40 was significantly associated with an increased risk of incident dementia among Black participants: 27.8% in medium (hazard ratio [HR] 1.69, 95% CI 1.07 to 2.68) and 33.5% in low (HR 2.07, 95% CI 1.32 to 3.24) compared with 17.3% in high Aβ42/40 tertile. The associations were somewhat weaker but showed the same trend among White participants: 20.3% in medium (HR 1.49, 95% CI 0.85 to 2.61) and 22.9% in low (HR 1.59, 95% CI 0.92 to 2.76) compared with 15% in high Aβ42/40 tertile. The interaction between Aβ42/40 and race was not statistically significant.

Conclusion

Among community‐dwelling, non‐demented older adults, plasma Aβ42/40 differs by race, although the association with dementia risk does not differ by race.
Surveying Willingness to Learn About and Share Results of Brain MRIs in South and East Asian Adults
Authors: Kota Karthik , Lee Woowon , Li Mei‐Ling , Marquez Melissa J , Estervil Jaunis J , Su Guibin J , Lopez Lisa Lanza , Dawson Allison , Sotelo Victor , Papas Julia , Bergren Stephanie , Hu William T.
Published: December 2023

Background

Dementia in South Asian (SA) and East Asian (EA) adults is often under‐reported by family due to stigma or under‐recognized by medical practitioners due to language barriers. Older SA and EA adults are also underrepresented in dementia research. While recruiting for a memory and aging study in the New York City/New Jersey (NYC/NJ) area, we noted hesitancy among older SA adults towards undergoing brain MRI analysis. We hypothesized that differences in attitudes towards MRI and brain health research may differ between older SA and other adults.

Method

We recruited a convenience sample of community‐dwelling adults in the NYC/NJ area from August 2022 to January 2023 to complete an anonymous survey on knowledge and attitudes towards MRIs and dementia. Topics and wording reflected concerns reported in the literature, including potential harms from MRI, desire to learn about incidental MRI findings, and stigmatizing beliefs. We specifically targeted SAs, but also recruited older Chinese and Korean adults.

Result

210 participants (n = 151 for 50+) completed the survey, including 69 (33%) SA adults. Chinese and Korean respondents had similar attitudes and perceptions, and were hereafter analyzed together as an EA group. Compared to non‐Hispanic White (White) respondents, SA and EA respondents were less interested in learning about incidental brain MRI findings. EA and White respondents were much more likely to share de‐identified brain MRI for research purposes than SA respondents, and this was mediated by future concern for dementia/stroke in EA, but not White, respondents. There was no difference in perception of MRI‐related harm or dementia‐related stigma.

Conclusion

SA and EA adults were both less interested in learning about incidental brain MRI findings than White adults, but the two Asian groups differed in willingness to share de‐identified MRI for research and concern for future dementia/stroke. In the absence of knowledge differences, these may be explained by cultural attitudes towards health and locus of control. Future studies on these factors are needed to promote research participation and dementia prevention among older SA adults.