bluuebunny/crossref_metadata_2025 huggingface dataset:
Prescription medications and co‐morbidities in late middle‐age are associated with lower executive function: Results from WRAP
Authors: Du Lianlian , Koscik Rebecca L , Chin Nathaniel A , Bratzke Lisa C , Cody Karly Alex , Erickson Claire M , Jonaitis Erin M , Mueller Kimberly D , Johnson Sterling C
Published: December 2020

Background

Aging is often accompanied by the accumulation of chronic illnesses such as diabetes, cardiovascular disease or hypertension and a corresponding increase in use of medications to manage these conditions. Polypharmacy (use of multiple prescription medications) is a growing health concern and has been associated with poorer clinical outcomes in older adults. This study investigates associations between comorbidities, polypharmacy and longitudinal cognitive performance in an Alzheimer’s disease (AD) risk‐enriched cohort, the Wisconsin Registry for Alzheimer’s Prevention (WRAP).

Method

Eligible WRAP participants included 1039 (free of dementia or clinical impairment not due to mild cognitive impairment (MCI) and with >=2 visits with cognitive composites, self‐reported health history, and concurrent medication records. Sums of prescribed medications and self‐reported co‐morbidities (include self‐ report over the lifetime) (Table 1) were calculated for each visit and converted to z‐scores for use in mixed effects models of cognition (covariates: age, gender, education, WRAT III reading recognition, practice and study site). Linear mixed effects analyses first examined whether associations between medications, comorbidities and cognitive z‐scores varied across cognitive domains of working memory, immediate recall, delayed recall, executive function, and a preclinical Alzheimer’s cognitive composite (PACC3) before examining associations with each cognitive composite. In secondary analyses, we examined whether number of medications and comorbidities interacted with each other or modified age trajectories.

Result

Sample characteristics are shown in Table 2 overall and by gender (mean(sd) baseline age=58.99(6.60)). More comorbidities were associated with more prescription medications (Figure 1). More comorbidities and medications were associated with lower executive function (β = ‐0.11, p=.002; β = ‐0.07, p = 0.047; Table 3); using z‐scores of 10th and 90th centile with model parameters, those with low co‐morbidities and medications performed an average of 0.39 SD higher than those elevated on both (Figure 2).

Conclusion

Associations between medications, comorbidities, and executive function suggest that persons with more comorbidities and medications may be either at increased risk of reaching clinical levels of impairment earlier than healthier, less medicated peers, or may have potentially reversible clinical impairment. Researchers should be aware of the possibility that medication use and comorbidity may impact cognitive performance (and by extension, adjudicated cognitive status).
Perivascular space dilation in white matter mediates a significant relationship between white matter hyperintensity burden and venous collagenosis
Authors: Lahna David , Schwartz Daniel L. , Woltjer Randy , Black Sandra E. , Roese Natalie E. , Dodge Hiroko H. , Boespflug Erin L. , Keith Julia , Gao Fuqiang , Ramirez Joel , Silbert Lisa C.
Published: December 2020

Background

Periventricular T2 MRI white matter hyperintensities (WMH) are commonly observed in older individuals and are associated with cognitive and motor decline. While likely vascular in origin, the specific etiology of WMH remains unknown. Vascular insufficiency due to venous collagenosis has been implicated. Collagenosis may also interfere with perivascular fluid flow leading to dilation of perivascular spaces (PVS). PVS are thus an unexplored potential mediating factor between collagenosis and periventricular WMH.

Method

Brain tissue from 25 Oregon Alzheimer’s Disease Center subjects was selected based on availability of in vivo 1.5 Tesla MRI (Table 1), which was used to quantify whole brain WMH burden. Three paraffin embedded 6μm thick coronal blocks of tissue per subject from anterior, middle and posterior white matter abutting the ventricle were stained with Masson’s Trichrome and Smooth Muscle Actin (SMA). Slides were scanned and an automated hue based algorithm identified 547 vessels and segmented them into blue collagen vessel walls, lumen holes within them and perivascular spaces outside them (Figure 1). Pearson correlation coefficients were calculated to assess relationships between PVS, periventricular WMH and collagenosis. Coregistered SMA images were used to classify vessels into veins (n=163) and arteries (n=251). Multiple linear regressions accounting for sex, age at death, and MRI to death interval followed by a Sobel test of mediation were calculated to determine the mediating effect of PVS on the relationship between collagenosis and periventricular WMH.

Result

Periventricular WMH volume, collagenosis and PVS were correlated with each other (p<.001) (Figure 1). In separate regression models, PVS and collagenosis in veins were significant predictors of WMH volume (p=.005, p=.007) but not in arteries (p=.256, p=.244). A Sobel test of the mediating effect of PVS on the relationship between collagenosis in veins and WMH burden was significant (p=.027) and the remaining direct effect of collagenosis on WMH was not significant (p=.21) (Figure 2).

Conclusion

Perivascular space dilation is an under recognized mechanism which may mediate the relationship between the development of venous collagenosis and periventricular WMH in an aged population.
The association of pain with dementia: Findings from the Mexican Health and Aging Study, 2012‐2015
Authors: Milani Sadaf Arefi , Rodriguez Martin A. , Samper‐Ternent Rafael , Wong Rebeca
Published: December 2020

Background

Mounting evidence suggests that pain is associated with cognitive decline; however, most of these studies are limited to high‐income countries. As the number of older adults living in low and middle‐income countries (LMICs) increases, by 2030 the majority of individuals living with dementia will reside in these countries. This makes Mexico, a LMIC facing a rapidly aging population, an important setting to investigate the relationship between pain and dementia.

Methods

Using data from the 2012 and 2015 waves of the Mexican Health and Aging Study (MHAS), a longitudinal, nationally representative study of Mexicans aged 50 and older, we assessed the association between pain and dementia. Participants who completed a direct interview, had complete information on pain, dementia, and relevant covariates, and who did not have dementia in 2012 were included (n=10,617). Pain was categorized as no pain, non‐persistent pain, and persistent pain. Persistent pain was defined as moderate or severe pain reported in both 2012 and 2015. Any other pain reported was categorized as non‐persistent pain. Dementia was classified using a modified version of the Cross‐Cultural Cognitive Examination. Multivariate logistic regression models were used to assess this association, adjusting for demographic, socioeconomic, and health factors.

Results

Overall, 4.9% of participants had dementia in 2015. Among participants with dementia, 51.7% reported non‐persistent pain and 22.5% reported persistent pain compared to 39.6% and 11.9% of those without dementia, respectively. After adjustment, both non‐persistent pain (OR: 1.87; 95% CI: 1.49, 2.34) and persistent pain (OR: 2.23; 95% CI: 1.67, 2.98) were associated with an increased odds of dementia, compared to no pain. Increasing age, ADL limitations, depression, diabetes, and stroke were associated with increased odds of dementia while higher educational attainment, consumer durables, and physical activity were associated with decreased odds of dementia.

Conclusions

There was a substantial amount of pain reported among Mexicans aged 50 and older with dementia. Reporting any type of pain was associated with an increased odds of dementia, compared to reporting no pain. Given that both pain and dementia decrease quality of life, future work should further evaluate this relationship to inform interventions.
Cholesterol‐dependent regulation of amyloid processing in neurons
Authors: Wang Hao , Kulas Joshua A. , Ferris Heather A. , Hansen Scott B.
Published: December 2020

Background

Apolipoprotein E (apoE), a cholesterol transport protein, is the most prevalent genetic risk factor in sporadic Alzheimer’s disease (AD). Cholesterol regulates the localization of Aβ‐producing enzymes with their substrate amyloid precursor protein (APP) in nanoscale lipid domains (rafts). Anecdotal evidence suggests apoE links to Aβ production through cholesterol’s effect on lipid rafts, but so far there has been little scientific validation of this link or the role of astrocyte‐derived cholesterol on neuronal Aβ production.

Method

The effects of astrocyte‐derived cholesterol on primary cortical neurons from wildtype and astrocyte‐specific knockout mice were determined using dSTORM super resolution imaging. The pair correlation (i.e. co‐localization) of APP with its hydrolytic enzymes (α‐, β‐, and γ‐secretases) was used to establish the mechanism of enzyme activation (substrate presentation) and indirectly show the likely resultant cleavage products Aβ and soluble APPα (sAPPα). The cleavage products Aβ and sAPPα were directly confirmed with ELISA. Inflammatory specific increases in cholesterol from primary astrocytes were measured using an fluorescent cholesterol assay.

Result

Super resolution imaging of primary neurons shows apoE utilizes astrocyte‐derived cholesterol to specifically traffic APP into lipid rafts where it interacts with β‐ and γ‐secretases to generate Aβ‐peptide. Inflammatory cytokines including IL‐1β and IL‐6 induce cholesterol synthesis in astrocytes. Treatment with cholesterol‐free apoE, or knockdown of cholesterol in astrocytes decreases cholesterol in cultured neurons and causes APP to traffic out of lipid rafts where it interacts with α‐secretase and gives rise to sAPPα, a neuronal protective product of APP. Sub‐cellular localizations of α‐, β‐, and γ‐secretases does not respond to changes in cellular cholesterol, suggesting the Aβ/sAPPα ratio is regulated by the trafficking of the substrate and not the enzymes.

Conclusion

Astrocytes regulate Aβ production through the delivery of cholesterol to neurons. This suggests that the cholesterol is used as a signaling molecule and the concentration is kept low in neurons to allow for astrocyte signaling. Under disease condition, pro‐inflammatory cytokines released by activated microglia induce cholesterol synthesis in astrocytes, contributing to increased Aβ production. This study establishes a mechanism that directly links apoE and inflammation with Aβ regulation and the risk of developing AD.
Plasma biomarkers predict amyloid pathology in cognitively unimpaired individuals
Authors: den Braber Anouk , Verberk Inge M.W. , Tomassen Jori , Stoops Erik , Mauroo Kimberley , Willemsen Gonneke , Nivard Michel G. , Van Berckel Bart N.M. , Scheltens Philip , Visser Pieter Jelle , de Geus Eco J.C. , Teunissen Charlotte E.
Published: December 2020

Background

Plasma biomarkers have shown promising for identification of patients with Alzheimer’s Disease (AD), but whether this holds for the earliest preclinical stages needs further study. We aimed to investigate the predictive value of plasma amyloid‐β1‐42/1‐40 and glial fibrillary acidic protein (GFAP) for identifying amyloid pathology in cognitively unimpaired individuals. We tested this using plasma samples collected at time of CSF/PET amyloid assessment and, using plasma samples collected 10 years before CSF/PET amyloid assessment.

Methods

We selected 151 subjects with normal cognition from the EMIF‐AD PreclinAD study. Amyloid status was defined using visual read of dynamic [18F]flutemetamol PET images or CSF amyloid‐β1‐42/1‐40 (Euroimmun) <0.065. For a subsample of participants (n=42), plasma samples were available that had been collected 10 years before CSF/PET amyloid assessment as part of the Netherlands Twin Register‐Biobank Study. Simoa assays were applied to measure amyloid‐β1‐42/1‐40 (ADx NeuroSciences‐AmsterdamUMC Amyblood) and GFAP (Quanterix) plasma levels. Pearson correlations were assessed between plasma, CSF and PET biomarkers. ROC curve analysis was used to determine the value of each plasma biomarker in predicting CSF/PET amyloid status.

Results

Amyloid‐positive individuals had lower plasma amyloid‐β1‐42/1‐40 and higher GFAP levels (Table 1). In samples collected at time of CSF/PET amyloid assessment, significant correlations were found between plasma amyloid‐β1‐42/1‐40 and CSF (r=.22,p=.048) and PET (r=‐.23,p=.035) amyloid, and between plasma and CSF GFAP (r=.33,p=.002). Both plasma markers were able to discriminate amyloid status with similar negative predictive value (.90), with amyloid‐β1‐42/1‐40 showing higher sensitivity (.72) and GFAP higher specificity (.81). Combining the two did not improve results (Table 2). Plasma amyloid‐β1‐42/1‐40 and GFAP in samples collected 10 years prior to CSF/PET amyloid assessment were also able to discriminate amyloid status (Table 3). In addition, correlations between these and biomarker levels from plasma collected at time of PET/CSF amyloid assessment were modest for amyloid‐β1‐42/1‐40 (r=.36, p=.018), and high for GFAP (r=.82, p<0.001).

Conclusion

Our data suggest that amyloid‐β1‐42/1‐40 and GFAP plasma markers can be used to identify AD pathology in cognitively unimpaired individuals at present and prospectively. In addition, the high negative predictive value indicates these markers’ potential as pre‐screening tools for secondary prevention trials.
A randomized controlled trial measuring changes in cerebral blood flow after levetiracetam in patients with Alzheimer’s disease
Authors: Musaeus Christian Sandøe , Zhao Li , Dai Weiying , Breton Jocelyn , Shafi Mouhsin , Alsop David C. , Press Daniel Z.
Published: December 2020

Background

Recent studies have shown that almost half of patients with Alzheimer’s disease demonstrate signs of epileptic activity as measured with EEG. Subclinical epileptic discharges can disrupt network activity, which is critical for long term memory. Therefore, suppressing epileptiform discharges may represent a novel therapeutic target for patients with Alzheimer’s disease. In the current randomized controlled trial, we recruited patients with mild Alzheimer’s disease and investigated the effect of a single administration of 2.5 mg/kg or 7.5 mg/kg of levetiracetam as compared with placebo on cerebral blood flow as measured with arterial spin‐labeling MRI (ASL‐MRI).

Method

We conducted a double‐blind, within‐subject crossover study in which nine participants with mild Alzheimer’s disease received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a randomized order across three sessions. Afterwards, participants underwent ASL‐MRI and performed a variety of neuropsychological cognitive tests. The regions with significant perfusion changes were analyzed with Statistical nonParametric Mapping (SnPM) toolbox.

Result

When comparing 2.5 mg/kg levetiracetam with placebo, we found significant (p<0.03 with family wise error corrected at a level of 0.05) increases in relative cerebral blood flow in a cluster involving both temporal lobes, including the hippocampus, with greater involvement on the left side. We found decreases in a cluster including the posterior cingulate cortex and precuneus. No clear changes were found following the higher dose. No significant differences in cognitive performance were found between the three groups, suggesting that the intervention neither worsened nor improved cognition.

Conclusion

In the current study, we found that in mild Alzheimer’s disease patients without any history of epilepsy a low dose of levetiracetam leads to changes in the cerebral blood flow in areas known to be affected early in the disease. One possible explanation could be that in mild AD, epileptic activity in the hippocampus leads to an excessive inhibition, and so relieving the inhibition with levetiracetam leads to an increased blood flow. These findings provide evidence of a potential beneficial effect of levetiracetam in patients with Alzheimer’s disease, but larger studies are needed, particularly with longer dosage schedules to determine whether there are any clinical improvements.
Exploring uptake of a university‐level educational intervention to prevent cognitive decline and reduce dementia risk: The Tasmanian Healthy Brain Project
Authors: Hill Edward , Bindoff Aidan , Bartlett Larissa , Summers Mathew J , Vickers James C
Published: December 2020

Background

Research suggests a substantial proportion of Alzheimer’s disease (AD) cases could be delayed, or even prevented, through modifying lifestyle factors. Low educational attainment has been associated with increased vulnerability to age‐related cognitive decline through reduced cognitive reserve. Strategies to enhance cognitive reserve in older adults may therefore provide cognitive resilience and reduce an individual’s AD risk. The Tasmanian Healthy Brain Project (THBP) is a longitudinal, prospective cohort study established to examine this possibility by following the cognitive health trajectory of older Australians engaging in university‐level education. To characterise predictors of uptake and inform recruitment for future educational interventions, we present an exploratory examination of university‐level education uptake in older Australian adults.

Method

Upon entry to the ongoing THBP, participants opted (non‐random assignment) to enrol in fee reduced university‐level education at the University of Tasmania. All participants undergo biennial assessments involving a comprehensive battery assessing neuropsychological, cognitive, psychological, social and clinical domains. For the current study, membership of experimental (intervention) group vs controls (non‐intervention) was treated as a binary outcome utilising logistic binomial regression. Baseline age, education, gender, prior cognitive reserve (PCR), APOE, Dementia Rating Scale and Hospital Anxiety and Depression Scale were included in linear and generalized additive models. Bayes Factors (computed using bridge sampling) were estimated to provide support for main effects models. All statistical analyses were performed in R (v3.6.1).

Result

Of 562 THBP participants, 437 (22.2%) elected to undertake university‐level education and 125 (77.8%) controls did not. On average, the interventional group was younger, more educated, displayed higher prior cognitive reserve and lower penetrance for APOE‐ε4 allele (Table 1). Logistic binomial regression suggested that of the variables assessed, age was the primary predictor of educational uptake (Figure 1).

Conclusion

In our models, a participant’s baseline age was the only variable to display an association with interventional group adherence to a university‐level education. In the current research climate where encouraging lifestyle risk factor modifications to reduce dementia risk, educational interventions may enhance cognitive resilience to age‐related cognitive decline, therefore recruitment efforts should be designed to target a wider age range in more demographically diverse populations.
TMS‐measures of cortical excitability are abnormal in amyloid‐positive MCI, relate to amyloid burden, and predict faster cognitive decline
Authors: Buss Stephanie S. , Macone Joanna , Li Gongri , McDonald Katherin , Shafi Mouhsin , Donohoe Kevin , Press Daniel Z. , Pascual‐Leone Alvaro , Fried Peter J.
Published: December 2020

Background

Alzheimer’s disease (AD) is associated with increased cortical excitability, including a risk of seizures and epileptiform discharges. Transcranial magnetic stimulation (TMS) can be used to index cortical excitability non‐invasively, and previous studies have revealed increased TMS excitability measures in AD. However, it is not yet known if TMS shows increased cortical excitability in amyloid‐β positive mild cognitive impairment (Aβ+ MCI), how TMS excitability relates to other AD biomarkers, or the extent to which cortical excitability may predict disease progression.

Method

TMS was applied to left motor cortex in 18 participants with Aβ+ MCI (aged 70±8.9, 9 females). Resting motor threshold (RMT) was measured as the minimum TMS intensity required to elicit a motor evoked potential on 5/10 trials. The primary analyses tested if RMT differed between Aβ+ MCI participants and a cohort of 36 older healthy controls (OHC; aged 63±9.7, 17 females). Separate linear models in Aβ+ MCI tested the relationship of RMT with hippocampal volume, Aβ burden on [18F]Florbetapir PET, and the Clinical Dementia Rating – Sum of Boxes (CDR‐SB). CDR‐SB was reassessed after 1‐2 years follow‐up, and a CDR‐SB Change Score was calculated to measure cognitive decline. The relationship with RMT and CDR‐SB Change Score was tested using a simple linear regression.

Result

The primary linear model controlling for age, gender, and scalp‐to‐cortex distance (SCD) showed a between‐group difference in RMT (B=3.62, p=0.023, Figure 1), with Aβ+ MCI showing lower RMT reflecting higher levels of cortical excitability. The covariate of SCD (B=1.92, p<0.001) was also significant. Secondary models with the same covariates showed that lower RMT was related to greater Aβ burden (B=‐0.43, p=0.016), but not hippocampal volume or CDR‐SB. In the subgroup of 10 Aβ+ MCI participants with longitudinal follow‐up, lower RMT predicted of worsening cognition on CDR‐SB Change Score (R=0.74, p=0.015, Figure 2).

Conclusion

Increased cortical excitability is found in Aβ+ MCI, is related to amyloid burden, and appears to predict greater longitudinal cognitive decline. TMS measures of cortical excitability may be useful as measures of target engagement for future therapies aimed at delaying disease progression in the early symptomatic stages of AD.
Augmenting cognitive assessment with instruction‐less eye‐tracking tests: A machine learning approach for detecting abnormal oculomotor biomarkers
Authors: Mengoudi Kyriaki , Ravi Daniele , Yong Keir XX , Primativo Silvia , Pavisic Ivanna M , Brotherhood Emilie V , Lu Kirsty , Schott Jonathan M , Crutch Sebastian J , Alexander Daniel C.
Published: December 2020

Background

Eye‐tracking technology is an innovative tool that holds promise for enhanced dementia screening, offering the potential of brief and quantitative assessment of cognitive functions. Critically, instruction‐less eye‐tracking tests may ameliorate some of the issues with complex test instructions and linguistic variations associated with traditional cognitive tests, and capture additional sensitive metrics of task performance. However, the extraction of relevant biomarkers from large, complex eye‐tracking datasets is non‐trivial. In this work, we introduce a novel automated way of extracting abnormal oculomotor biomarkers using machine learning from raw eye‐tracking data acquired during an instruction‐less cognitive test.

Method

A free‐viewing instruction‐less cognitive battery (5 minutes) was administered to healthy controls (N=553) and patients with a range of dementias (N = 30) [Figure 1]. Our method is based on self‐supervised representation learning: a deep neural network is initially trained to solve a pretext task that has well‐defined available labels. Here the pretext task is to identify distinct tasks ‐ scene perception, reading, episodic memory for scenes ‐ in healthy individuals from eye‐tracking patterns. Figure 2 visualises some features of eye‐tracking patterns that correspond to particular tasks. Once trained, this network encodes high‐level semantic information which is useful for solving other problems of interests (e.g. dementia classification) [Figure 3]. The extent to which eye‐tracking features of patients with dementia deviate from healthy behaviour is then explored, followed by a comparison between self‐supervised and handcrafted representations on discriminating between controls and patients.

Result

Based on the results of the handcrafted features, patients with dementia had significantly lower scanpath lengths than controls (z = ‐276.56, SE = 97.09, p =0.00439), consistent with less extensive and efficient scanning of the presented stimuli. The self‐supervised learning features showed higher performance in discriminating dementia patients from controls (F1 score (95% CI: [0.78, 0.82]) vs standard handcrafted features [0.62, 0.67]).

Conclusion

These results suggest that instruction‐less eye‐tracking tests can detect dementia status, even in the absence of explicit task instructions. We reveal novel self‐supervised learning features that are more sensitive than handcrafted features in detecting performance differences between participants with and without dementia across a variety of eye‐tracking‐based cognitive tasks.
Activity and TREM2‐dependent phagocytic cup formation by microglia in the mouse cortex
Authors: Martin‐Avila Alejandro , Tiberi Alexia , Zhao Ruohe , Weinhard Laetitia , Cheng Zongyue , Gan Wen‐Biao
Published: December 2020

Background

Microglia are the main innate immune cells capable of engulfing dead cells and cellular debris in the brain. Trem2 receptor is expressed in microglia and plays an important role in phagocytosis. This receptor has been linked to Alzheimer’s disease and involved in the uptake of amyloid plaques by microglia. However, how microglia engulf dead cells and the role of Trem2 in this process remain unclear.

Method

We used two‐photon microscopy to image microglia engulfing of dead cells in the primary motor cortex of Cx3cr1
gfp/+ mice, Cx3cr1gfp/+:Trem2‐/‐ mice, Cx3cr1gfp/+:Trem2R47H/+ mice, and ThyGCaMP6 mice. These mice were placed on a custom made, free‐floating treadmill and subjected to five motor‐running sessions over one hour. Electron microscopy was used to determine the ultrastructure of microglial phagocytic cups engulfing dead cells. We manipulated neuronal activity by using AAV viral infection to express ChR2 in thalamic neurons or by administrating MK‐801 or muscimol in the motor cortex.

Result

Our time‐lapse imaging data show that microglial processes form phagocytic cups to engulf dead cells within tens of minutes in the motor cortex during running. Ultrastructural examination of phagocytic cups confirmed the engulfment of dead cell body by microglial processes as revealed by live imaging. Pharmacological inhibition of neuronal activity was sufficient to prevent running‐dependent phagocytic cup formation. On the other hand, optogenetic stimulation of thalamocortical projections induced the formation of microglial phagocytic cups. In Trem2‐deficient mice and Trem2 R47H mice, running‐dependent phagocytic cup formation was reduced as compared to wild type controls. There was an increase of propidium iodide (PI)‐positive cell bodies in Trem2 deficient/haplodeficient mice comparted to the control mice.

Conclusion

These findings reveal that the formation of phagocytic cups by microglia is dependent on neuronal activity and the Trem2 receptor in the mouse cortex. They also suggest that the lack of dead‐cell clearance mediated by microglia might play a role in the pathogenesis of Alzheimer’s disease.
Partial mitochondrial complex I inhibitors as disease‐modifying therapeutics for Alzheimer’s disease
Authors: Trushin Sergey , Stojakovic Andrea , Chang Su‐Youne , Trushina Eugenia
Published: December 2020

Background

Alzheimer’s Disease (AD) has no effective treatments, and recent clinical trials focused on prevention of amyloid beta (Ab) production have consistently failed. Alternative approaches are urgently needed. We developed small molecules partial mitochondrial complex I (MCI) inhibitors and demonstrated that their application prevents the development of cognitive and behavior phenotype, improves LTP, reduces oxidative stress and inflammation, and restores glucose uptake and utilization in the brain in mouse models of familial AD. Efficacy could be monitored in vivo using translational biomarkers FDG‐PET, 31P NMR and blood biomarkers.

Method

We conducted extensive structure‐activity relationship (SAR) studies to characterize novel classes of compounds partial MCI inhibitors including a new lead compound C458. Target engagement, selectivity and specificity of new compounds were established using multiple in vitro and cellular assays including SPR, competitive and direct binding, proteomics and pull down experiments.

Result

We demonstrated that the lead C458 directly binds and competes with the FMN for binding to complex I. In primary neurons and mouse brain tissue, single dose administration of C458 activates AMPK‐a, autophagy, Sirtuins 1 and 3, and upregulate PGC‐1a leading to enhanced mitochondrial biogenesis. In vivo, chronic administration of C458 had no detectable toxicity at therapeutic doses. C458 has excellent oral bioavailability and blood–brain‐barrier penetration. C458 was remarkably clean in 250 kinase panel. Finally, in pre‐symptomatic APP/PS1 mice, treatment with C458 resulted in cognitive protection and improved long‐term potentiation after 6 months of chronic oral administration (25 mg/kg/day), decreased oxidative stress and inflammation. Furthermore, APP/PS1 mice treated with C458 showed a significant increase in metabolic rates and glucose brain uptake and utilization detected with translational FDG‐PET imaging as well as an enhancement of ATP production in the brain measured in vivo with 31P NMR.

Conclusion

Mechanistic studies demonstrate that MCI inhibitors induce protective stress response increasing mitochondrial biogenesis and turnover, augmenting cellular energetics and the protection against oxidative stress, and engage other mechanisms that intersect with the pathways involved in longevity and health extension. Our studies demonstrate that modulation of MCI activity using novel FMN MCI inhibitors improves bioenergetics in the brain and averts cognitive decline in Alzheimer’s Disease representing novel therapeutic approach.
The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND): A longitudinal public health research program targeting dementia risk reduction
Authors: Bartlett Larissa , Doherty Kathleen , Farrow Maree , Bindoff Aidan , Kim Sarang , Eccleston Claire , Hill Edward , Alty Jane , King Anna E , Vickers James C
Published: December 2020

Background

A substantial proportion of risk for age‐related dementia may be attributable to modifiable factors. The ISLAND Project responds to international calls (Lancet Commission, World Health Organisation) to investigate the effectiveness of public health strategies for reducing dementia risk. This large longitudinal and interventional cohort study will evaluate a sustained public health campaign to mitigate behaviours associated with dementia risk. The Tasmanian population comprises approximately 500,000 urban, rural and remote residents and has a prevalence of factors associated with dementia risk that is higher than Australian norms. This contained island population offers a unique opportunity for recruitment, cohort maintenance and tracking changes in participants’ dementia risk profile over time.

Method

The ISLAND Project aims to recruit 10% of Tasmanians aged 50 and over (target n=20,000). Participants will be offered a series of educational and community‐based interventions to build self‐efficacy in dementia risk management. Engagement with these interventions will be evaluated. Self‐report, online surveys administered annually will track changes in participants’ physical and mental health, social functioning, dementia risk literacy and risk‐related behaviours. Cognitive screening and biomarkers (e.g. blood) will be collected biennially. The Dementia Risk Profile (DRP) will support and track behaviour change. The DRP provides a traffic‐light indicator of personal risk and recommended actions, based on WHO risk reduction guidelines. The DRP can be updated every six months and printed to support health consultations.

Result

The ISLAND Project launched in June 2019. Preliminary data collected between October and December 2019 indicate the ambitious recruitment target is feasible, with 10,729 registering interest in the study, of whom 4,937 have provided research consent (73% female, median age 62 years). Participants’ postcodes signify reasonably representative geographical distribution (urban 77%, rural 22%; Figure 1) and current baseline data include: background and health (n=4270), knowledge (n=3781) and attitudes about dementia risk (n=3588), depression (n=3541) and the DRP (n=3269).

Conclusion

The ISLAND Project aims to translate, into a public health setting, research evidence that reducing dementia risk can be achieved through modifying behaviours. Findings from this population‐based approach to dementia risk reduction will be used to inform future public health policy and practice.
Linking central auditory deficits to cognitive decline in mice with amyloid deposition
Authors: Wang Aaron , Lawlor Jennifer , Fogelson Kelly , Kuchibhotla Kishore
Published: December 2020

Background

Alzheimer’s disease (AD) is a form of dementia that is characterized by the progressive loss of cognitive capacity, including the loss of executive functions and memory. There is growing evidence suggesting that hearing loss and dementia are tightly linked, with recent studies showing that hearing loss is independently associated with accelerated cognitive decline. However, the neural mechanisms linking hearing loss to AD‐related pathologies and subsequent cognitive decline remain unknown.

Method

We will test the hypothesis that amyloid pathology impacts feedforward sensory processing in primary auditory cortex (A1). We performed in vivo two‐photon calcium imaging in awake, head‐fixed APPswe/PS1dE9 (APP/PS1) mice to investigate how AD pathology impacts central auditory processing. APP/PS1 mice express chimeric mouse/human amyloid precursor protein (APP) and mutant presinilin‐1 (PS1). These transgenes target neurons of the central nervous system and lead to the rapid accumulation of soluble amyloid beta and subsequent plaque deposition in cortical and hippocampal areas. Our study uses the fine‐scale tonotopic arrangement of excitatory neurons in A1 as an assay for feedforward sensory integration. With two‐photon calcium imaging, we have the spatial and temporal resolution to monitor the activity of hundreds of neurons simultaneously with single‐cell resolution.

Result

Preliminary data collected from 11 mice (7 APP+, 4 WT) suggests clear differences in the processing of feedforward sensory information, namely differences in the tonotopic arrangement of neurons in A1 between WT and APP/PS1 mice.

Conclusion

Future work will investigate how AD pathology affects sensorimotor learning. Learning rates will be monitored in APP/PS1 mice trained on a go/no‐go stimulus recognition task. To probe the neural computations that are critical for the selection of auditory cues during behavior, excitatory networks in A1 will be monitored using two‐photon calcium imaging while animals perform the task. This study hopes to elucidate neural mechanisms of how amyloid beta pathology impacts central auditory processing, and thus, mechanistically link hearing loss, AD‐related pathologies and cognitive impairments.
Impact of unreliability on intraclass correlation coefficient and its implications for studies with clustered data
Authors: Ma Yue , Jonaitis Erin M , Hulle Carol A , Koscik Rebecca L , Jones Richard N , Carlsson Cynthia M.
Published: December 2020

Background

Studies using cerebrospinal fluid (CSF) biomarkers often combine CSF samples collected at different centers or assayed in different laboratories or batches, creating a clustered data structure. Such clustering needs to be controlled in the analysis of the combined data. Intraclass correlation coefficient (ICC), i.e., the ratio of the between‐cluster variance over the total variance, is used to quantify the magnitude of the clustering. The between‐cluster variance is a mix of (a) difference in CSF samples and (b) variation in measurement (i.e., unreliability). Thus the observed ICC (under unreliability) would deviate from the true ICC (under perfect reliability). We studied (1) how the observed ICC would deviate and (2) the statistical performance in its estimation.

Method

Aim (1) was achieved through mathematical derivations based on Classical Test Theory. Aim (2) was achieved using a simulation study to evaluate the relative bias, empirical standard error (se), and root mean square error (RMSE) in the sample estimates of the observed ICC, under three reliability levels (0.7, 0.8, 0.9), three true ICC values (0.1, 0.3, 0.5), and two cluster sizes (10, 50), with 10,000 replications for each condition.

Result

Aim (1): The observed ICC is greater than the true ICC. The inflation, represented as their ratio, is a function of reliability, true ICC, and cluster size (Figure 1). It decreases with increased reliability or true ICC, or decreased cluster size (Figures 2, 3). Aim (2): The sample estimates had very small negative bias (within 3%), which generally decreased with increased cluster size or true ICC, or reduced reliability. The empirical se and RMSE decreased with increased cluster size, but their relations with reliability or true ICC varied across conditions (Table 1).

Conclusion

The observed ICC is deviated (inflated), but unbiased. Using reliable measure is crucial when CSF samples have low variation between clusters to avoid substantial inflation in ICC. Increasing cluster size would exacerbate the inflation, yet would also increase estimation accuracy and efficiency. Such tradeoffs should be considered with planning CSF sample collection and assay. These findings can be applied to clustered data of other outcomes such as imaging and cognition.
Retinal capillary perfusion in autosomal dominant Alzheimer’s disease
Authors: Singer Maxwell , Ringman John M , Laughlin Alice , Chu Zhongi , Wang Ruikang , Kashani Amir H
Published: December 2020

Background

Alterations of perfusion in small blood vessels may be early events during Alzheimer’s disease (AD) development and such differences may be visible in the retina. The purpose of the current study is to quantify retinal capillary density and blood flow in subjects with autosomal dominant Alzheimer’s Disease (ADAD)‐causing mutations during the preclinical and clinical disease stages using optical coherence tomography angiography (OCTA).

Method

This is a cross‐sectional study of subjects with PSEN1 or APP mutations (n = 12) and age‐matched controls (n = 21). Mutation carriers were split into early‐stage (ES) and late‐stage (LS) groups based on an age‐adjusted cutoff of ‐4 (four years before predicted age of dementia onset based on mutation variant). Each subject underwent OCTA imaging of the central 3x3mm macula. Capillary density was measured using previously validated custom software and quantified as vessel skeleton density or VSD. Capillary blood flow was measured using a novel metric called flux which is derived from non‐binarized OCTA images and represents total number of red blood cells passing through the voxel per unit time. Statistical analysis was performed using generalized estimating equations adjusting for gender and correlation of two eyes from the same subject.

Result

ES carriers (n = 4, 3 w/CDR = 1, 1 w/CDR = 0.5) had a significantly greater flux (0.161 ± 0.006) than controls (n = 21, 0.144 ± 0.01, p = 0.02) and LS carriers (n = 12, CDR scores 0.5 – 3, 0.144 ± 0.008, p<0.0001, Figure 1). In contrast, there was no difference between flux of LS carriers and controls. ES carriers also had significantly greater capillary density (VSD) than controls (0.157 ± 0.006 vs 0.153 ± 0.005; p = 0.017).

Conclusion

ES carriers of PSEN1 or APP mutations demonstrate increased retinal capillary blood flow when compared to controls that was not present in LS carriers. Our data suggests that there is increased retinal perfusion in ES carriers, possibly resulting from increased blood flow in perfused capillary segments and recruitment of dormant capillary segments. These findings are consistent with studies showing cerebral hyperperfusion in pre‐symptomatic individuals with ADAD and indicate this may extend to the retina.
Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid‐beta, tau, and neurotrophic dysfunction
Authors: Yang Cuicui , Zhang Lan
Published: December 2020

Background

Targeting proteinopathies is involved in the protective effects of pharmacologic agents to treat Alzheimer’s disease (AD). Cornel iridoid glycoside (CIG) are the effective component from Cornus officinalis. The aim of the present research was to explore the potential effects of CIG on β‐amyloid (Aβ) and tau pathology and its underlying mechanisms in APP/PS1/Tau triple transgenic (3×Tg) mice.

Method

We intragastrically administered 16‐month‐old 3×Tg mice with CIG (100 and 200 mg/kg) for 2 months. Morris water maze and object recognition tests were used to detect learning and memory abilities. Thioflavin‐S staining and immunohistochemistry were used to detect amyloid plaques and Aβ40/42. Western blotting assay was performed to determine the expression of related proteins in the cerebral cortex and hippocampus of mice.

Result

The results showed that CIG treatment improved learning and memory impairment in 3×Tg mice. CIG decreased amyloid plaque deposition, Aβ40/42 and the expression of full‐length amyloid precursor protein; and increased the levels of ADAM‐10 (a‐secretase), neprilysin (NEP) and insulin degrading enzyme (IDE) in the brain of 3×Tg mice. Moreover, CIG reduced tau hyperphosphorylation, and elevated phosphorylation level of GSK‐3β at Ser9 and methylation of PP2A catalytic subunit C in the model mice. CIG increased the expression of nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF) and phosphorylated cAMP‐responsive element binding protein (p‐CREB) in the brain of 3×Tg mice.

Conclusion

CIG ameliorated learning and memory deficit via reducing Aβ content and, tau hyperphosphorylation and increasing neurotrophic factors in the brain of 3×Tg mice. These results suggest that CIG may be beneficial for AD therapy.
Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) study and Tata Longitudinal Study on Aging (TLSA): Study protocols
Authors: Sundarakumar Jonas , Chauhan Ganesh , Rao Girish N , Sivakumar Palanimuthu T , Rao Naren P , Ravindranath Vijayalakshmi ,   SANSCOG and TLSA Investigators
Published: December 2020

Background

Population‐based, prospective, longitudinal, aging and cognition studies are an important approach to understand the pathophysiology of normal and pathological cognitive aging. However, till date there are no comprehensive cohort studies from the Indian population, examining clinical, cognitive phenotypes and associated genetic and neuroimaging correlates.

Method

The Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) study and the Tata Longitudinal Study on Aging (TLSA) are envisioned as parallel and synchronized, prospective, community‐based cohort studies in India – rural and urban, respectively – with long term follow‐up over many years, for comprehensive evaluation of risk and protective factors associated with cognitive changes due to normal ageing, dementia and other related disorders (n=10,000 for SANSCOG and n=1,000 for TLSA). Both the study cohorts comprise of cognitively healthy individuals aged ≥ 45 years. However, they have distinct population characteristics. Participants in the SANSCOG study are recruited from the villages of Srinivaspur Taluk in Kolar District in southern India, through an area sampling strategy, whereas, those in TLSA are recruited through convenience sampling, from urban Bangalore. Participants are evaluated with detailed clinical, neurocognitive, lifestyle, anthropometric, biochemical and genetic assessments in the baseline visit and during periodic follow‐up visits. End‐to‐end digitization has been done for all the assessments. GWAS, Whole Genome Sequencing & MRI (resting fMRI, structural MRI, DTI & MRS) is being done in a subset of the SANSCOG study cohort (n=1,000) and the entire TLSA cohort (n=1,000).

Result

These parallel cohort studies will generate a database comprising of genetic, biochemical, clinical, neuroimaging and neurocognitive data that can help in further exploration of the pathophysiology of normal and pathological cognitive aging using systems biology‐based approaches. Though these two cohorts are contrasting with respect to socio‐economic status, migration, literacy and lifestyle, the harmonization in the assessments across the two studies offers a unique opportunity to compare outcome measures across these two groups.

Conclusion

SANSCOG and TLSA studies are landmark cohort studies in India, which employ a combined multi‐level approach, spanning genotype to phenotype and will be able to provide reliable biomarkers to predict the risk factors for development of dementia in the Indian population.
Altered serum levels of proteins involved in beta‐amyloid clearance in the aftermath of the Kumamoto magnitude 7.3 earthquake
Authors: Uchida Kazuhiko , Sato Tadashi , Tanaka Motomi , Oniki Kentaro , Saruwatari Junji , Itai Yaeko , Takahashi Noriaki , Matsuda Hiroshi , Osame Mitsuhiro
Published: December 2020

Background

Our previous studies revealed that apoA‐I, transthyretin, and complement component 3 (C3) in serum were associated with cognitive decline, and that atrophy of atrophy of the medial temporal structures was associated with decreased levels of apoA‐I1,2). Increased risk of dementia was observed in the aftermath of disaster like earthquake and tsunami. The 2016 Kumamoto Earthquake, which was featured twice strong earthquakes of seismic intensity 7 and aftershock activities in the long period, produced house damaging and persistent and strong stress in people. In present study, we analyzed the levels of the blood‐based biomarker and hippocampal atrophy in the aftermath of the earthquake.

Method

We obtained the data of serum biomarker levels and MRI imaging at every 6 month during the 3 years after the 2016 Kumamoto Earthquake and also those at 6 months before the earthquake. In total, 111 serum marker‐test results were obtained from 6 months before to 42 months after the earthquake. Atrophy of the medial temporal structures was measured by the semi‐quantified VSRAD score in about 1,000 subjects.

Result

Serum transthyretin and C3 levels were decreased at 6 months after the earthquake, and continue lower levels until 12 months. We calculated values of composite makers of these 3 proteins and determined cut‐off level which discriminated MCI from non‐demented control. The positive rate using cut‐off value before the earthquake was increased to 44% at 6 months, and it reduced to 10% at 18 months after the earthquake. Significant reduction of the hippocampal volume in male at 24 and 36 months was observed, on the other hand, there is no significant change in hippocampal volume in female. Interstingly, seum ApoA‐I levels were decreased in male and increased in female after the earthquake, and significant relationship between apoA‐I levels and hippocampal volume.

Conclusion

Blood‐based biomarkers related to Aβ clearance might be useful to grasp cognitive decline prior to neuroimaging changes in progression of cognitive impairment. Resources: 1) Lui S, et al. Alzheimers Dement (Amst), published online Dec 18 (2018); 2) Uchida K, et al. Alzheimers Dement (Amst) 1:270‐280 (2015).