bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal tau burden partially mediates synergistic influence of vascular risk and amyloid‐beta on cognitive decline in clinically normal older adults
Authors: Yau Wai‐Ying Wendy , Shirzadi Zahra , Rabin Jennifer S. , Properzi Michael J , Schultz Aaron P. , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Chhatwal Jasmeer P.
Published: December 2022

Background

Vascular risk is increasingly recognized as an important contributor to late‐life cognitive impairment. Elevated vascular risk and amyloid‐beta (Aβ) burden have been synergistically associated with greater cognitive decline, however the underlying mechanisms remain unclear. We examined the combined effects of baseline vascular risk and Aβ on longitudinal tau burden. We further investigated the extent to which tau accumulation mediates the synergistic effects of increased vascular risk and Aβ on prospective cognitive decline.

Method

We included data from 175 older adults (cognitively unimpaired at baseline) from the Harvard Aging Brain Study (HABS) (Table 1). Baseline Aβ burden was measured with Pittsburgh Compound‐B (PiB) PET. Baseline vascular risk was quantified using the office‐based Framingham Heart Study general cardiovascular disease risk score (FHS‐CVD). Tau burden was measured longitudinally with Flortaucipir‐PET in inferior temporal cortex (ITC), an early site of neocortical tau accumulation and a region of interest based on prior work. Cognition was assessed longitudinally using Preclinical Alzheimer Cognitive Composite (PACC). Using linear mixed effects models, we examined the interactive effects of FHS‐CVD and Aβ on longitudinal ITC tau accumulation, adjusting for age, sex and APOE ε4 status. Next, we examined the FHS‐CVD*Aβ interaction using floodlight/Johnson‐Neyman analysis to determine the level of Aβ at which effects on ITC tau accumulation became significant. Using moderated mediation analysis, we further examined whether tau accumulation mediated the FHS‐CVD*Aβ interactive effects on PACC decline.

Result

Individual ITC‐tau trajectories are shown in Figure 1. We found an interaction between higher baseline FHS‐CVD and elevated Aβ with greater longitudinal ITC‐tau accumulation (Figure 2; Table 2). Floodlight analysis showed the FHS‐CVD*Aβ interaction became significant (p<0.05) at PiB‐DVR>1.22, lower than the conventional threshold for amyloid‐positivity (PiB‐DVR>1.32). Moderated mediation models revealed ITC‐tau accumulation partially mediated (30%) the effect of FHS‐CVD on PACC decline at high (PiB‐DVR=1.85: β=‐0.48, p<0.001) but not low (PiB‐DVR=1.17: β=‐0.16, p=0.09) levels of baseline Aβ (Figure 3).

Conclusion

Vascular risk may interact with Aβ to promote cognitive decline partially through accelerating tau accumulation, even at subthreshold levels of Aβ. Further studies are needed to elucidate other mechanisms that mediate the remaining effects of this clinically important interaction.
Translational potential of JAX hAPOE AD mouse model: Phenotypic characterization of cognitive function and amyloid beta
Authors: Altemus Jesse
Published: December 2022

Background

APOEe4 is the greatest genetic risk factor for late onset Alzheimer’s Disease (LOAD). The product of this gene, apolipoprotein E isoform ε4, has been characterized as a lipid transporter and many of its receptors and mechanisms have been identified. Studies have shown that APOEe4 exacerbates accumulation of Aβ peptides and correlates with a decline in cognitive function in humans. We investigated the translational feasibility of the humanized APOE3 (JAX #029018) and APOE4 (JAX #027894) mouse model on two hallmark pathologies of LOAD: cognitive decline and b‐amyloid (Aβ) generation in brain.

Method

Novel object recognition (NOR), open field (OF), and CatWalk analyses were conducted in 18 month old transgenic mice with humanized APOEe3 homozygous (B6(SJL)‐ApoEtm1.1(APOE*3)Adiuj/J), APOEe3/4, or APOEe4 homozygous genes (B6(SJL)‐ApoEtm1.1(APOE*4)Adiuj/J). NOR analyses included discrimination index, OF center zone time, whereas CatWalk included mobility measures including cadence and speed. Aβ38, Aβ40, and Aβ42 analyses were assessed in brain and plasma.

Result

No differences were detected in NOR discrimination index, NOR combined object exploration time, or OF center zone time across sex or genotype. OF mean speed was lower in APOE3/4 mice compared to APOE4 mice. Aβ38 was not detected in any group. Hippocampal Aβ42 was significantly lower in APOE3/4 mice compared to APOE4 and APOE3 mice. No differences were detected in hippocampal Aβ40 or Aβ42/40 ratios. Plasma Aβ40, Aβ42, and Aβ42/40 were lower in females relative to males. Analyses based on sex and genotype indicated that plasma Aβ40 and Aβ42 were lower in APOE3 females vs APOE3 males, and Aβ42/40 was lower in APOE3 females vs every other group.

Conclusion

APOE3/4 heterozygosity may confer a protective effect against Aβ42 deposition in the hippocampus, and female APOE mice consistently exhibit lower plasma Aβ. Translational applicability to humans on measures of cognitive decline and hippocampal Aβ42 deposition at 18 months (human age equivalent ∼56 years) for APOE mice is limited.

Acknowledgements: Research supported by NIA R01AG57931 and RF1AG059093
Traumatic Brain Injury Exacerbates Retinal Alzheimer’s Disease Histopathology in the TgF344 Rat Model
Authors: Vergara M. Natalia , Secora Conner N , Vielle Anne , Wang Athena Ching‐Jung , Lenhart Patricia , Salcedo Ernesto , Johnson Noah R , Ahmed Md. Mahiuddin , Chial Heidi J , Boyd Timothy D. , Potter Huntington
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative condition of the central nervous system that affects both the brain and the retina, and can lead to visual impairment. However, the factors that modulate AD pathophysiology leading to the wide range of clinical presentations are not well understood. Notably, traumatic brain injury (TBI), which can arise from sport concussions, military combat and other causes, is associated with a 2.3‐fold higher risk of developing AD and AD‐related dementias. Yet the pathophysiological link between TBI and AD remains poorly understood. In this study we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology, by taking advantage of a transgenic rat model (Tg‐F344‐AD) shown to recapitulate the main features of human AD pathology, and combining it with a controlled cortical impact paradigm of repetitive mild TBI (rmTBI).

Methods

Male Tg‐F344‐AD rats and F344 wild‐type controls were aged to 12 months and randomly selected to undergo a two‐time unilateral controlled cortical impact (2xCCI; one week apart) that mimics rmTBI, or a sham procedure. The animals were sacrificed at four months post‐CCI to evaluate long‐term effects of the procedure, and the eyes were collected and analyzed using immunofluorescence and standard histological staining techniques to evaluate Alzheimer’s histopathology.

Results

Histopathological analyses at four months post‐impact confirm the presence of AD markers in Tg‐F344‐AD retinas. Moreover, we found that AD increases Aβ deposition and neuroinflammation in the retina, and that TBI enhances the severity of this phenotype by increasing the formation of dense core amyloid plaques.

Conclusions

We have developed and characterized a model to study the pathophysiology of AD in relation to rmTBI in the retina, which could lead to better treatments and to the development of retinal biomarkers for improved AD diagnosis.
Statin responder analysis for precision prevention of Alzheimer’s Disease
Authors: Torrandell‐Haro Georgina , Branigan Gregory L , Rodgers Kathleen E. , Brinton Roberta Diaz
Published: December 2022

Background

Previously we identified reduced risk of Alzheimer’s Disease (AD) in statin users (Torrandell‐Haro et al. 2020). Identifying the subgroup of responders is an important step towards a precision statin therapy approach. This study aimed to investigate the effect of statin therapy on the incidence of Alzheimer’s Disease (AD) and other age‐related neurodegenerative diseases (NDD) by therapy, sex, and age group. Moreover, it sought to identify and describe responder vs non‐responder phenotypes to statin therapy based on demographic characteristics, comorbidity burden, and drug exposure.

Method

A retrospective analysis was conducted using a US‐based insurance claims dataset of 53 million participants. Inclusion criteria included participants aged 45 years old or older, with no prior history of NDD before statin use, and with claims enrolled for at least 6 months prior and 3 years after start of statin therapy. A propensity score‐matched based on age, gender, region, comorbidities and cci was applied for group assignment. Records were surveyed for a diagnosis of AD 1 year after statin exposure. Sensitivity analyses for the detection of responders based on comorbidities and drug combinations were conducted.

Result

Of the 1,293,952 participants who met inclusion criteria, 646,976 participants were exposed to statin therapy and were propensity score‐matched to 646,976 patients without exposure. Statin use was associated with a decreased risk of AD (RR [95% CI]: 0.54 [0.52–0.57]; P < .001) and other NDD. Additionally, men exhibited a greater risk reduction than women, which was driven by atorvastatin and simvastatin. Responders had a higher incidence of obesity and asthma whereas non‐responders were predominantly female and had an overall higher incidence of cardiovascular and cerebrovascular comorbidities.

Conclusion

Statin use was associated with a reduced risk of AD and other NDD, replicating previous results. Non‐responders were predominantly women with a high incidence of cardiovascular comorbidities. Characterization of responders to statin exposure advances a precision prevention approach, in which prescription guidelines consider neurological health and are adapted for at‐risk populations.

This work was supported by the National Institute on Aging (grant R01AG057931), and the Women’s Alzheimer’s Movement and the Center for Innovation in Brain Science to Dr Brinton.
Deep Learning Registration with Scan‐temporal Consistency May Improve Detection of Alzheimer’s Disease Progression
Authors: Dong Mengjin , Xie Long , Wang Jiancong , Das Sandhitsu R. , Wolk David A. , Yushkevich Paul A.
Published: December 2022

Background

Structural changes in Alzheimer’s disease (AD) can be detected as atrophy in the medial temporal lobe (MTL), which is normally studied by applying volumetric or deformation‐based morphometry (DBM) to longitudinal scans. However, conventional DMB methods are computationally intensive and may not estimate the atrophy accurately due to the noise in the longitudinal images, e.g., head motion or MRI artifacts. We hypothesize that deep learning models can be trained to estimate atrophy from longitudinal MRI scans and are more sensitive to biological changes rather than artifactual.

Method

Two models were trained on longitudinal T1 MRI from 155 ADNI participants and tested on 326 participants. First, a deep learning‐based registration model Voxelmorph (Balakrishnan et al., 2019) was applied to generate a deformation field to calculate MTL atrophy rate for each pair of images. Hypothesizing that noise is independent of time while neurodegeneration is time dependent, we then extended Voxelmorph to incorporate a loss that encourages the model to correctly infer the input scan temporal order (STO). In addition, in order to preserve the deformable registration nature of Voxelmorph, it’s weights were held fixed during network training, and instead a U‐Net reconstruction network was introduced, to synthesize inputs to Voxelmorph. Models were compared with a DBM method ALOHA (Das et al., 2012).

Result

Voxelmorph generated atrophy measurements comparable to ALOHA in terms of differentiating AD stages (Figure 2) and STO consistency (Table 2). Voxelmorph + STO model has increased STO consistency and can more significantly differentiate disease stages (in absolute terms), especially between the normal controls and preclinical AD.

Conclusion

Deep learning‐based registration method Voxelmorph achieves comparable performance in longitudinal analysis of subtle changes as in DBM method ALOHA. With the introduction of a scan temporal order loss and reconstruction network, the model achieves higher sensitivity to disease stage, potentially because it learns to discount longitudinal changes that are related to noise and artifact. This may lead to more sensitive biomarkers for disease monitoring in clinical trials of early AD.
The Potential Alzheimer’s Disease Drug, GM‐CSF, Enhances the Anti‐Viral Immune Response and Reduces Mortality in a Mouse Model of COVID‐19
Authors: Kendall Lon V. , Boyd Timothy D. , Sillau Stefan H , Bosco‐Lauth Angela , Markham Neil , Fong Derek , Clarke Penny , Tyler Kenneth L. , Potter Huntington
Published: December 2022

Background

COVID‐19 results in increased expression of inflammatory cytokines and Alzheimer’s disease (AD) biomarkers of neuronal damage, but inflammation‐targeting clinical trials have yielded poor to mixed results. Our studies of other disorders with an inflammatory component, including AD, chemobrain, Down syndrome, normal aging, and West Nile Virus infection, showed that treatment with the ‘pro‐inflammatory’ cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in humans or mouse models alleviated clinical, behavioral, and pathological features. Most recently, we completed a Phase 2 clinical trial (NCT01409915) using sargramostim/Leukine (rhuGM‐CSF) in mild‐to‐moderate AD participants, which showed that three weeks of sargramostim treatment improved MMSE scores and improved ATN blood biomarkers of AD pathology (Potter et al., 2021). Therefore, we proposed that human GM‐CSF may be repurposed to promote both the innate and adaptive immune responses in COVID‐19 patients to reduce viral load and mortality.

Method

We investigated GM‐CSF’s effects in eight‐week old male and female human ACE2 (hACE2) transgenic mice infected intranasally with 104 PFU of SARS‐CoV‐2 virus and followed them for 14 days. Mice received daily IP injections of either recombinant murine GM‐CSF or saline. Viral titers, anti‐spike protein antibody levels, and mortality were assessed.

Results

Intranasal inoculation of hACE2 transgenic mice with 104 PFU SARS‐CoV2 virus resulted in high viral titers in lungs and brains and over 85% mortality. GM‐CSF treatment beginning one day post‐infection increased anti‐spike protein antibody titers, lowered mean lung viral titers proportionately (p = 0.0020), and increased the odds of long‐term survival by up to 5.8‐fold (p = 0.0358), compared to saline.

Conclusion

GM‐CSF represents a new approach to the treatment of COVID‐19 by recruiting inflammation and the immune system to attack SARS‐CoV‐2 infection and promote survival.

GM‐CSF is likely to have a significant advantage over current approaches to the treatment of COVID‐19, including anti‐virus monoclonal antibodies, drugs designed to inhibit viral replication, and immunosuppressants, because, unlike short‐term antivirals, it activates the endogenous immune system, with likely long‐term increases in immune memory required for protection against re‐infection,

Based on its mode of action as a natural stimulator of the immune response, GM‐CSF should be effective against all current and future SARS‐CoV‐2 variants.
Racial Differences in BMI and Cognitive Performance in Persons Aged 80 and Older
Authors: Trammell Antoine R , Goldstein Felicia C , Parker Monica W , Hajjar Ihab
Published: December 2022

Background

There is evidence that late‐life BMI is protective against cognitive decline. As Alzheimer’s disease (AD) study samples do not reflect the general population, it is not clear if there are racial differences this finding. We investigated late‐life BMI and cognitive performance in a biracial sample.

Method

Using ANOVA or chi‐square, demographic, physical, and cognitive test scores were compared in persons age 80 and older by race. Cognitive groups were based on global CDR. Normal cognition (NC) was defined per global CDR = 0 and impaired cognition per global CDR = 0.5,1,2, or 3. Mixed models adjusted for age, sex, and education with BMI as the predictor evaluated cognitive test scores by race for study visits from 2005 to 2020. The significance level for all tests was p < 0.05.

Result

Data for 9,581 persons was analyzed. The sample was mostly white (86.6% vs. 13.41%, <.0001). AA were younger (86.4 vs. 86.9, <.0001), had higher BMI (26.8 vs. 25.5, <.0001), fewer years of education (13.4 years vs. 15.3 years, <.0001), and lower MOCA scores (18 vs 21, <.0001) than whites. In AA, mixed models showed associations between higher BMI and executive function (Trial Making Test‐B:β = ‐1.51,p<.01) and episodic memory (Craft delayed: β = .07,p = .01). In whites, there was an association between higher BMI and picture naming (Multilingual Naming: β = .09,p = <.01), attention (Trail Making Test‐A:β = ‐.12, p = 0.3), and working memory (Number span, backward: β = .03,p = .01).

Conclusion

Late‐life BMI is associated with improved cognitive domain performance that vary by race. Further study is needed to prospectively replicate the findings in multiethnic cohort and explore factors underlying the differences.
Optimizing Placebo Effects in Depressed Older Adults: Enhancing Processing Speed and Executive Functioning with Computerized Cognitive Training
Authors: Premnath Pranitha Y , Egglefield Dakota , Schiff Sophie , Bursky Mikell , Zilcha‐Mano Sigal , Rutherford Bret R , Sneed Joel R
Published: December 2022

Background

Major Depressive Disorder (MDD) is a leading cause of disability and a severe public health concern for older adults. Slowed processing speed (PS) and executive dysfunction (ED) often complicate antidepressant treatment response in this population. Treatment non‐response in older adults with PS deficits may be caused by failure to form expectations about treatment, suggesting that targeting PS deficits prior to antidepressant treatment may restore the capacity to form expectations and improve treatment response. One way of improving PS may be through the use of computerized cognitive training (CCT), through structured drills and repeated practice. This study aims to 1) determine whether PS mediates the relationship between CCT and expectancy, and 2) assess the effects of CCT and expectancy manipulations on depressive symptoms in geriatric populations.

Method

100 older adults (≥ 60 years; Hamilton Rating Scale for Depression (HRSD) score ≥ 20) with PS deficits will be randomized to either CCT or control (Solitaire) for 4 weeks. Both conditions will train for 25 minutes/day, 7 days/week. At the conclusion of this four‐week period, patients will be randomized to high versus low expectancy treatment conditions. Patients assigned to the low expectancy condition will be told they will receive either placebo or escitalopram. Patients assigned to the high expectancy condition will be told they will receive escitalopram for 8 weeks. All participants will receive escitalopram for 8 weeks. Neuropsychological assessments will be completed at baseline, week 4, and week 12; MRI acquisition at baseline and week 4. Clinical assessments will be conducted weekly throughout the study.

Results

Recruitment is in progress and is expected to be completed by April 2024 followed by data analysis.

Conclusion

In light of the increased use of virtual healthcare platforms in response to the pandemic, developing accessible, technology driven interventions that address antidepressant non‐response and improve quality of life in older adults is increasingly important. This novel experimental, therapeutic approach tailors existing interventions to optimize outcomes for antidepressant treatment in late‐life depression and addresses significant challenges in current geriatric mental health research.
Perceived neighborhood safety and aesthetic quality are associated with cognitive change over time
Authors: Hyun Jinshil , Qin Jiyue , Katz Mindy J. , Derby Carol A. , Wang Cuiling , Sliwinski Martin J. , Lipton Richard B.
Published: December 2022

Background

Identifying factors that contribute to cognitive decline is critical to the design of interventions to help older adults maintain independence. Although several studies have investigated associations between neighborhood characteristics and cognitive decline, these studies have not properly considered practice‐related cognitive gains (i.e., retest effects), which may hamper accurate estimation of aging‐related cognitive decline over time. This study examined whether subjective neighborhood characteristics were associated with longitudinal changes in processing speed, an early marker of cognitive aging and impairment, after accounting for retest effects.

Method

The analysis sample includes 316 individuals enrolled in the Einstein Aging Study (mean age = 78; 67% females; 46% non‐Hispanic Whites, 40% non‐Hispanic Blacks). Neighborhood characteristics, including perceived neighborhood safety, aesthetic quality, and social cohesion, were measured at enrollment from self‐reports (range = 1 poor to 5 excellent). Processing speed was assessed using the brief, smartphone‐administered Symbol Search Test, and was completed 6 times per day for 16 days. The 16‐day protocol was repeated every year for three years. Double negative exponential models were used to estimate the relation of neighborhood characteristics to asymptotic performance (i.e., fastest response time) at baseline and asymptotic change (the rate in which asymptotic performance changes across years).

Result

Results suggested that perceived neighborhood safety was associated with better (i.e., faster) baseline asymptotic performance after controlling for demographic information and individual‐ and neighborhood‐level socioeconomic status (Table 1). A one‐point increase in perceived safety was associated with a 115 millisecond faster asymptotic response time at baseline. Neighborhood safety and aesthetic quality were associated with greater decline in asymptotic response time: asymptotic response time decreased by 42 milliseconds (for safety) and 60 milliseconds (for aesthetic quality) per year for a one‐point increase in safety and aesthetic quality (Figure 1).

Conclusion

Perceived neighborhood characteristics were associated with both baseline cognitive performance and rates of cognitive change for a three‐year period among community‐dwelling older adults. It is possible that a disordered neighborhood environment may act as a chronic stress leading to long‐term cognitive decline. Future studies need to examine psychosocial and behavioral mechanisms to identify targetable area for intervention.
Improving Vascular Functions by Bioreactive Nanoparticles for Treatment of Alzheimer’s Disease
Authors: Park Elliya , Li Lily Yi , He Chunsheng , Abbasi Azhar Z. , Ahmed Taksim , Foltz Warren D. , Rauth Andrew M. , Fraser Paul , Henderson Jeffrey T. , Wu Xiao Yu
Published: December 2022

Background

Developing effective disease‐modifying treatment for Alzheimer’s disease (AD) remains a tremendous challenge due to its multifactorial nature involving multiple pathologic signaling pathways in addition to ineffective drug delivery through the blood‐brain barrier (BBB).1 With this in mind our group has developed multifunctional bioreactive nanoparticles (Ab‐TP‐MDNPs), consisting of anti‐amyloid β antibody (Ab) linked to brain‐penetrating terpolymer (TP) and manganese dioxide (MnO2) nanoparticles (MDNPs), that are shown to reduce oxidative stress in AD brains.2 Given the early occurrence of oxidative stress, hypoxia, and vascular dysfunction in AD brains,3,4 we investigated the therapeutic effects of Ab‐TP‐MDNPs on reducing neuroinflammation and vascular dysfunction in an AD mouse model.

Method

A transgenic mouse model of AD (TgCRND8 species) and wildtype littermates (WT) were treated with intravenous (i.v.) injection of Ab‐TP‐MDNPs (twice/week, 100 µmol Mn/kg b.w.) or vehicle for 2‐weeks. Oxidative and inflammatory biomarkers were examined using immunohistochemistry and enzyme‐linked immunosorbent assay (ELISA). Vascular function before and after the treatment was studied via high resolution magnetic resonance imaging (MRI). Cerebral blood flow (CBF) was assessed using FAIR (flow‐sensitive alternating inversion recovery) technique. BBB permeability was measured via T1 mapping re‐acquisition prior to and following i.v. injection of gadolinium‐diethylenetriamine penta‐acetate (Gd‐DTPA) at 1.2 mmol/kg

Result

Ab‐TP‐MDNPs treatment significantly decreased inflammatory cytokines and activation of microglia and astrocytes markers (reactive microglia: hippocampus by 69% and cortex by 59%, reactive astrocytes: hippocampus by 32% and cortex by 33%). In addition, Ab‐TP‐MDNPs treatment improved CBF (cortex by 19% and subcortex by 35%) and vessel leakage by 29% in the cortex of AD mouse brains.

Conclusion

Ab‐TP‐MDNPs treatment reduced neuroinflammation and vascular dysfunction in an AD mouse model. These findings suggest a new multimodal strategy for AD treatment and encourage further development of such approach for complex neurologic diseases.

Reference:

1. Panza F, Lozupone M, Logroscino G, Imbimbo BP. Nature Reviews Neurology. 2019;15(2):73‐88.

2. He C, Ahmed T, Abbasi AZ, et al. Nano Today. 2020;35:100965.

3. Sweeney MD, Montagne A, Sagare AP, et al. Alzheimer’s & Dementia. 2019;15(1):158‐167.

4. Nortley R, Korte N, Izquierdo P, et al. Science. 2019:eaav9518.
The effects of sub‐threshold depression and anxiety symptoms on fluid cognitive performance in older adults: an exploratory analysis
Authors: Farris Kristen M , Parsey Carolyn M , Hanson Angela J
Published: December 2022

Background

Clinical anxiety and depression have well‐understood cognitive effects, but less is known about sub‐threshold symptoms. This study explored differences in cognition between older adults with sub‐threshold symptoms of depression or anxiety in comparison to those with no symptoms and investigated whether the COVID‐19 pandemic or APOE4 carrier status contributed to these symptoms.

Method

72 older adults (age 64.33±6.3) completed the Patient Health Questionnaire (PHQ‐9), Generalized Anxiety Disorder scale (GAD‐7), and NIH Toolbox Cognition Battery (NIHTB‐CB). Participants were split into a Pre‐COVID Group (participation before March 2020) and a Post‐COVID Group. Subjects were also split based on their mood assessment scores. Those who scored 0 on the PHQ‐9 (“None” Group) were separated from those who scored 1–4 (“Some” Group). The same process was performed for the GAD‐7 assessment. Age‐corrected NIHTB‐CB scores were compared between groups for both mood assessments by ANCOVA using SAS Studio software, adjusting for education level.

Result

There were no significant differences in PHQ‐9 or GAD‐7 scores between Pre‐ and Post‐COVID groups, nor did mood symptoms differ by APOE4 status (p’s>.05). The PHQ‐9 “Some” Group produced higher scores on the Fluid Cognition Composite than the “None” Group (111.11±2.24 and 102.57±2.81, respectively; p = .023). This was driven by significantly better performances on Pattern Comparison (PC; p = .014) and a trend of better performance on Dimensional Change Card Sort task (DCCS; p = .054). Reaction times were also faster for the “Some” Group on DCCS (p = .002) and PC (p = .002) tasks. No significant differences were found for GAD‐7 subgroupings.

Conclusion

Anxious and depressive symptoms did not differ between COVID‐19 or APOE4 groups. While sub‐threshold anxiety did not affect cognition, those with some depressive symptoms performed better on fluid cognitive measures, specifically tests of processing speed, than those with no symptoms. Further analysis exploring the relationship between components of these two mood assessments and fluid cognitive performance is warranted.
HMGB1‐Mediated Senescence and Brain Inflammation Contributes to Cognitive Dysfunctions
Authors: Gaikwad Sagar , Kayed Rakez
Published: December 2022

Background

High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein, which is excessively released by glial cells during aging and Alzheimer’s Disease (AD). The extracellular HMGB1 serves as a key initiator of neuroinflammation, which is linked to exacerbated cognitive impairments in AD. Importantly, aging ‐ the strongest risk factor for AD is characterized by a chronic, low‐grade inflammation known as inflammaging. Evidence suggests that senescent cells (SC) accumulate with aging and are characterized by an apoptosis‐resistant, arrested cell cycle with a distinct “inflammatory” phenotype also known as senescence‐associated secretory phenotype (SASP). However, the precise etiology of inflammaging in tauopathies remain largely unknown.

Method

We used brain tissues from AD patients and hTau mouse model and performed immunoflourescence, microscopy, astrocyte cell cultures, pharmacological inhibition of HMGB1 in vitro and in vivo in a hTau mouse model to examine role of HMGB1 in senescence, brain inflammation and cognitive dysfunctions. We scored cellular senescence, inflammation, tau pathology (phospho‐tau, tau oligomers, neurofibrillary tangles), Synaptic and postsynaptic proteins, and cognitive functions (Y‐maze and novel‐objective recognition tests).

Result

In this study, we demonstrate that (1) HMGB1 release is linked to advanced age in hTau tauopathy mice. (2) HMGB1 release is a hallmark of senescent cells both in mice and humans. (3) Astrocytes display a senescence‐like phenotype in the brains of patients with AD. (4) Pathological tau oligomers (TauOs) exposure triggers astrocyte senescence through HMGB1 release, which mediates paracrine senescence in adjacent cells and potentiates inflammatory SASP. (5) Inhibition of HMGB1 release using ethyl pyruvate (EP) and glycyrrhizic acid (GA) results in decreased astrocyte senescence and neuroinflammation. (6) Importantly, despite the developed tauopathy and cognitive deficits in 12‐month‐old hTau mice, EP+GA treatment significantly decreased SCs loads in the brain, reduces inflammaging, and thus ameliorated cognitive deficits. Collectively, our data suggest that HMGB1 release promotes inflammaging, and cellular senescence, which could represent an important pathomechanism in the progression of aging‐related diseases, including AD. Future studies are warranted to develop safe and effective therapeutic strategies to control inflammaging and enhance healthy lifespan in patients with tauopathy.

Conclusion

The data suggests that HMGB1 release is a key pathomechanism in AD.
Characteristics of Cognitive Function Changes and Related Factors in Individuals with Cognitive Impairment during the Pandemic of COVID‐19
Authors: Choi Jin‐Hui , Kim Hyegeum , Seo Wan‐Seok , Koo Bon‐Hoon , Sung Hyung‐Mo , Cheon Eun‐Jin , Kim Ji Yean , Jeong Hyun‐Seok , Kim Younggyo
Published: December 2022

Background

This study aimed to explore the characteristics and factors related to changes in cognitive function in vulnerable individuals with cognitive impairment affected by the coronavirus disease 2019 (COVID‐19) pandemic.

Method

Among patients who visited a local university hospital with subjective cognitive complaints, those who had been tested for cognitive function at least once after the onset of COVID‐19 and tested regularly at least three times within the last 5 years were included. Finally, 108 patients were included in this study. They were divided into groups according to whether the Clinical Dementia Rating (CDR) was maintained/improved and deteriorated. We investigated the characteristics of the changes in cognitive function and related factors during COVID‐19.

Result

When comparing CDR changes before and after COVID‐19, there was no significant difference between the two groups (p = .317). Alternatively, the main effect of the time when the test was conducted was significant (p<.001). There was also a significant difference in the interaction between the groups and time. When the effect of the interaction was analyzed, the CDR score of the maintained/improved group significantly decreased before COVID‐19 (1st–2nd) (p = .045). After COVID‐19 (2nd–3rd), the CDR score of the deteriorated group was significantly higher than that of the maintained/improved group (p<.001). MMSE recall memory and changes in activity during COVID‐19 were significantly associated with CDR deterioration.

Conclusion

Memory dysfunction and decreased activity during the COVID‐19 pandemic are strongly related to the deterioration of cognitive impairment.
Resilience and Reserve mechanisms underlying clinical‐cognitive progression in Dominant Inherited Alzheimer’s Disease.
Authors: Llibre‐Guerra Jorge J , Ma Yinjiao , Aschenbrenner Andrew J. , Xiong Chengjie , Hassenstab Jason J. , Gordon Brian A. , Benzinger Tammie L.S. , Fagan Anne M. , Perrin Richard J. , Morris John C. , McDade Eric , Bateman Randall J.
Published: December 2022

Background

Prevention of Alzheimer’s dementia may encompass both avoiding the AD pathological processes (resistance) and coping with AD pathology (resilience). Increasing evidence implicates resistance/resilience factors (e.g., level of education, socio‐economic status [SES], physical activity [PA]) occurring through life as potential modifiers of age at symptom onset (AAO) and rate of cognitive decline to dementia. The extent to which life course factors may influence disease progression in Dominantly Inherited Alzheimer’s Disease (DIAD) remains unknown.

Methods

We aimed to examine the influence of life‐course factors on clinical‐cognitive decline and MRI hippocampal volume in individuals with DIAD enrolled in the Dominantly Inherited Alzheimer Network. A total of 310 mutations carriers (195 asymptomatic and 111 symptomatic [CDR>0]) self‐reported education, work complexity, SES, and PA at baseline and completed longitudinal clinical‐cognitive measures, CSF biomarker studies (Aβ‐42, p‐tau‐181, t‐tau), structural MRI and Aβ‐PET imaging. The influence of life‐course risk factors on AAO, cognitive performances, and hippocampal volume were analyzed using linear mixed models.

Result

In mutation carriers (MC), adjusting for age, PiB‐PET SUVR, and sex, lower clinical disease severity as measured by CDR‐SB was associated with higher levels of education (p = 0.04), PA (p = 0.01) and SES (0.002). Similarly, MC with higher educational levels (p = 0.02) and SES levels (p = 0.001) exhibited larger hippocampal volume despite no differences in PiB‐PET SUVR. Longitudinally, MC with higher levels of education, PA, and SES showed better performance and slower cognitive decline in memory and executive function prior to symptom onset (CDR>0), but a similar decline rate after symptom onset.

Conclusion

Life‐course factors, like higher education, PA, and SES may promote brain resistance and clinical resilience to AD pathology in DIAD. A model of cognitive reserve in DIAD may help to identify how social and behavioral factors influence the progression of AD pathophysiology and explain how a variety of factors may enhance resistance to pathology, delay AAO, and cognitive decline rate.
Differential modulation of amyloid‐beta levels by psychotropic medications in an in vitro model of Alzheimer’s disease
Authors: Aleksynas Robertas , Sastre Magdalena
Published: December 2022

Background

Preclinical studies suggest that psychotropic drugs (e.g. antidepressants, benzodiazepines) can affect amyloid‐β (Aβ) levels, yet mechanisms remain unclear. We aimed to determine the effects of common psychiatric drugs on Aβ generation and clearance in an in vitro model of Alzheimer’s disease (AD).

Method

The effects of a range of psychotropic drugs on Aβ generation and clearance were assessed in N2a/APP695swe cells, a neuroblastoma cell line overexpressing APP with the Swedish mutation. Cells were incubated for 24h with either fluoxetine (selective serotonin reuptake inhibitor (SSRI); 1‐10μM), venlafaxine (serotonin‐norepinephrine reuptake inhibitor (SNRI); 0.1‐10μM), mirtazapine (α2‐adrenergic antagonist; 1‐25μM), phenelzine (monoamine oxidase inhibitor (MAOI); 10‐50μM) or nordiazepam (benzodiazepine (BNZ); 1‐25μM). Aβ42 levels were quantified in conditioned media using an enzyme‐linked immunosorbent assay (ELISA). Amyloid precursor protein (APP) processing was studied using western blots (WBs), including expression of different secretases, full‐length APP, C‐terminal fragments (CTFs) in membrane preps and APP soluble‐α in media. Neprilysin and insulin degrading enzyme (IDE) expression was quantified as major Aβ clearance factors.

Results

Certain drugs increased Aβ levels; in particular, Venlafaxine (SNRI) and nordiazepam (BNZ) elevated Aβ42 at 10 µM, due to increased amyloidogenic APP cleavage. Conversely, the anti‐depressant drug fluoxetine (SSRI; 10 µM) reduced Aβ42, concomitant with reduced β‐secretase (BACE1) and presenilin‐2 expressions. Mirtazapine (α2‐adrenergic antagonist) and phenelzine (MAOI), on the other hand, did not modulate Aβ levels.

Conclusion

Certain psychotropic medications, i.e. nordiazepam (BNZ) and venlafaxine (SNRI) can increase Aβ levels, while fluoxetine (SSRI) can reduce them. This results from the effects of these drugs on Aβ generation rather than clearance. This is important, as the administration of these drugs could affect AD‐risk.
A Text Message Intervention to Support Latino Dementia Family Caregivers (CuidaTEXT): Feasibility study
Authors: Perales Jaime
Published: December 2022

Background

Latino family caregivers experience disproportionately poor health outcomes and access to caregiver support. We aimed to test the feasibility, acceptability, and preliminary efficacy of CuidaTEXT: a tailored text message intervention to support Latino dementia family caregivers.

Method

CuidaTEXT is a six‐month, bilingual, and bidirectional intervention tailored to caregiver needs (e.g., education, problem‐solving, resources). We enrolled 24 Latino caregivers in a one‐arm trial, and assessed feasibility, acceptability, and preliminary efficacy within six months.

Result

Recruitment took 61 days and enrollment took 20. None of the participants unsubscribed from CuidaTEXT, and 83.3% completed the follow up survey. Most participants (85.7%) reported reading most text messages thoroughly. Participants reported high levels of satisfaction with the intervention (3.6 on a scale from 1 to 4). CuidaTEXT helpfulness was high (3.5‐3.8 on a 1 to 4 scale). Compared to baseline, at six months caregiver behavioral symptom distress (0‐60) decreased from 19.8 to 12.0, and depression (0‐30) from 8.8 to 5.4 (p<0.05).

Conclusion

CuidaTEXT demonstrated high levels of feasibility, acceptability, and preliminary efficacy among Latino caregivers. The next logical step is CuidaTEXT’s efficacy‐testing.
Interferon hypersensitivity in the brain of a Down syndrome preclinical model
Authors: Mumford Paige , Farrell Clíona , Salih Dervis , Tybulewicz Victor L , Fisher Elizabeth , Wiseman Frances K
Published: December 2022

Background

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21). People with DS have altered neuroinflammation, including abnormal microglial morphology and elevated cytokines. The peripheral immune system is also different in DS, including an over‐activated interferon response likely due to four genes encoding interferon receptors being located on Hsa21. How this affects neuroinflammation is unknown. The “ex vivo” model system of organotypic brain slice cultures (OBSCs) derived from mouse brain can be used to model neuroinflammation. We created OBSCs from a DS preclinical mouse model containing three copies of the interferon receptor genes, and treated them with interferon‐β to investigate if this model had a hyper‐sensitive interferon response in the brain.

Method

The Dp(16)2Tyb (Dp(16Mis18a‐Runx1)2TybEmcf, MGI 5703800) mouse strain was used, which has the region Mis18a‐Runx1 on mouse chromosome 16 in three copies, containing ∼33 Hsa21 orthologous genes including the four interferon receptor genes. Cortico‐hippocampal OBSCs were prepared from Dp(16)2Tyb pups at age P8‐P9, grown in culture and treated at DIV14 with interferon‐β for 24‐hours. Slices were used for western blotting or qPCR, and conditioned media used for ELISAs.

Result

Dp(16)2Tyb OBSCs treated with interferon‐β had a significantly elevated response to treatment compared to treated wild‐type littermates, with higher expression of interferon‐stimulated genes in slice tissue and higher levels of CXCL10 protein secreted into the conditioned media.

Conclusion

We found that Dp(16)2Tyb OBSCs displayed a hypersensitive interferon response. The apparent candidate genes for this interferon hypersensitivity are the four interferon receptor genes encoded on Hsa21. How this interferon hypersensitivity effects neuroinflammation in the presence of amyloid pathology is unknown. Next, we will cross the Dp(16)2Tyb with the AppNL‐G‐F mouse model of amyloid pathology to investigate how interferon hypersensitivity alters neuroinflammation in response to amyloid pathology.
Translational Inhibition of Multiple Neurotoxic Proteins Leads to Improved Cognition in Alzheimer’s Disease
Authors: Fang Cheng , Hernandez Priscilla , Liow Kore , Chen Michael , Zetterberg Henrik , Blennow Kaj , Maccecchini Maria L.
Published: December 2022

Background

Overexpression of neurotoxic proteins drives downstream events that dysregulate axonal transport, lead to inflammation, nerve cell death, and loss of function. By inhibiting the translation of amyloid precursor protein, tau and alpha‐synuclein, our drug restored axonal transport, lowered inflammation, and protected nerve cells from dying in animal models. Buntanetap’s reversal of the toxic cascade leading to nerve cell death did preserve and/or restore full function in 7 different animal models of neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Method

In a double blind, placebo controlled Phase2a study, early AD patients were randomized into 80mg Buntanetap (n = 10) or placebo (n = 5) QD for 25±2 days. We evaluated the safety, pharmacokinetics of Buntanetap, biomarkers, and its efficacy.

Result

In clinical trials, Buntanetap was safe in over 200 subjects, both healthy volunteers and AD/PD patients. In our recent double‐blind, placebo controlled Phase2a study, patients randomized to either 80mg QD Buntanetap or placebo we measured biomarkers in AD patients and showed that Buntanetap can lower neurotoxic proteins, improve axonal integrity and synaptic function, and lower inflammation. Buntanetap has also improved AD patients’ cognitive functions as measured by ADASCog11 and WAIS coding test after 25±2 days treatment.

Conclusion

These encouraging data support our further development of Buntanetap as a potential treatment for Alzheimer’s disease. We are planning three double‐blind, placebo‐controlled studies, a short 3‐month dose‐finding trial and two long‐term 12‐ and 18‐month trials in early and moderate AD patients.
Translational Inhibition of Multiple Neurotoxic Proteins Leads to Improved Motor Function in Parkinson’s Disease
Authors: Fang Cheng , Hernandez Priscilla , Liow Kore , Chen Michael , Zetterberg Henrik , Blennow Kaj , Maccecchini Maria L.
Published: December 2022

Background

Parkinson’s disease (PD) is a neurodegenerative disorder that affects predominately dopaminergic neurons in substantia nigra. Although alpha‐synuclein (αSYN) is the main component of Lewy bodies, TDP‐43, Aβ and tau are also detected in PD. Buntanetap has been shown to inhibit the translation of multiple neurotoxic proteins such as amyloid precursor protein, tau and alpha‐synuclein. It been shown in animal models to restore axonal transport, lower inflammation and protect nerve cells from dying. By reversing the toxic cascade leading to nerve cell death, Buntanetap preserves and restores full function in 7 different animal models of neurodegenerative diseases including PD.

Method

In our double‐blind, placebo‐controlled, dose‐finding Phase 2a trial, 5 different doses of Buntanetap (5mg, 10mg, 20mg, 40mg and 80mg QD) were tested compared to control after25±2 days treatment. Buntanetap’s safety, pharmacokinetics, biomarkers and efficacy were evaluated.

Result

In clinical trials, Buntanetap was safe in over 200 subjects, both in healthy volunteers and in AD/PD patient. In PD patients, Buntanetap lowers neurotoxic proteins, improves axonal integrity and synaptic function, and lowers inflammation. Buntanetap improves PD patients’ mobility shown by MDS‐UPDRS and WAIS coding test after 25±2 days treatment. Of the 5 different doses, 10 & 20mg Buntanetap QD showed the best clinical outcomes.

Conclusion

These data supported us getting regulatory approval to develop next stage pivotal studies in larger population and for longer durations. The FDA consented us to move the development into two phase 3 clinical studies – one in early and one in advanced PD. Our first pivotal trial intends to treat 450 early PD patients at 1:1:1 ration for 10mg, 20mg Buntanetap QD or placebo for 6 months duration.
Depletion of the AD risk gene SORL1 causes endo‐lysosomal dysfunction in human microglia
Authors: Mishra Swati , Knupp Allison , Young Jessica E. , Jayadev Suman
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder which is currently incurable. Prior to well‐established neuropathological changes in AD, enlarged early endosomes are cytopathological hallmark of AD and strong genetic evidence links genes involved in intra‐cellular trafficking, mediated by endo‐lysosomal pathway, to increased AD risk, suggesting that this pathway is integral to the pathogenesis of AD. We recently identified SORL1, an intracellular sorting receptor as a potential regulator of this pathway. Using CRISPR/Cas9 to deplete SORL1 in human induced pluripotent stem cells (hiPSCs), we showed that loss of SORL1 results in enlarged early endosomes in (hiPSCs)‐derived neurons, but not microglia. This model replicates the earliest AD cytopathology and our data underscores important cell‐type specific differences in response to loss of SORL1. Building on this study, we further examined alterations in lysosomal function, with altered expression of SORL1 in hiPSC‐derived microglia.

Method

Isogenic hiPSC lines that are deficient in SORL1 were generated and differentiated into microglia using previous published protocols. Lysosome function was assayed by examining lysosome morphology, lysosomal trafficking of fibrillar Aβ, lysosomal degradation, lysosome enzyme activity and lysosomal exocytosis. Lysosome morphology and number were measured using immunocytochemistry, confocal microscopy and Cell Profiler and Image J software. To assess Aβ transport into lysosomes, pH sensitive fluorescent dye, Phrodo, conjugated to Aβ, was used. Lysosomal degradation was measured using a proteolysis sensitive fluorogenic substrate, DQ‐BSA. Fluorescence intensity of both Phrodo and DQ‐BSA was measured using flow cytometry. Lysosome enzyme activity and exocytosis assays were performed using previously published protocols.

Result

Loss of SORL1 results in increased lysosome size and decreased lysosome number in SORL1 KO microglia indicating altered lysosome function. In support of this idea, we observed decreased lysosomal degradation, trafficking of Aβ to lysosomes and lysosomal enzyme activity and also decreased lysosomal exocytosis in SORL1 KO microglia.

Conclusion

Overall, our results have unraveled a previously unexplored function of the AD risk gene SORL1 in human microglia and our work indicates that maintaining homeostatic balance in the endo‐lysosomal network impacts diverse CNS cell types. Our study will define the endo‐lysosomal network in general, and SORL1 in particular, as a novel therapeutic target for AD.