bluuebunny/crossref_metadata_2025 huggingface dataset:
Aggregated amyloid‐beta1‐42 infusion following pinealectomy induces Alzheimer’s diseases in rats in a week:behavioral and biochemical impairments
Authors: Tchekalarova Jana Dimitrova , Georgieva Irina , Tzoneva Rumiana , Angelova Violina T
Published: December 2023

Background

The hormone melatonin has an advantage compared to other available antioxidants for the therapeutic strategy of Alzheimer diseases (AD) because of its protective activity against amyloid‐beta (Ab1‐42) accumulation, low toxicity effect, and readly passage through the blood‐brain barrier. The beneficial role of melatonin supplementation on Ab neurotoxicity in rat models of AD was reported in many studies. Recently, we reported that melatonin could compensate AD pathology in the icvAb1‐42 rat model via antioxidant activity in the hippocampus. The present study aimed to propose a new rat model of AD‐like pathology induced by pinealectomy followed by icvAb1‐42 infusion a week later.

Method

The theraupetic ffect of melatonin treatment (10 mg/kg, i/p/ for 20 days), starting simultaneously with pinealectomy until decapitation of animals, was assesed on behavioral impairments.Circadian oscillations of motor activity were assesed for 24 h by actimeter. Cognitive functions were explored bt the Y maze and the object recognition test (ORT). The expression of abeta‐amyloid and the activity of the enzyme responsible for Abeta accumulation ‐ gama‐secretase were studied in the frontal cortex and the hippocampus by ELISA method.

Result

Rats with pinealectomy+icvAβ1‐42, treated chronically with vehicle, demonstrated reduced motor activity with blunted circadian rhythms of locomotion in the actimeter concomitant with impaired spatial working memory and reference memory. Melatonin supplementation corrected those mentioned above behavioral and biochemical abnormalities to the control values.

Conclusion

Our results suggest that the modified pinealectomy+Aβ1‐42 rat model produces AD pathology as early as a week after icv Aβ1‐42 infusion. In contrast, melatonin treatment had a beneficial effect on behavioral and biochemical impairments. Therefore, this model might be helpful in the exploration of novel melatoninergic analogs with potential activity against AD pathology.

Acknowledgements: This work was supported by the National Science Fund, project KP‐06‐H63/11 and KP‐06‐Н31/16.
A machine learning model to predict progression from subjective cognitive decline to mild cognitive impairment and dementia: a 12‐year follow‐up study
Authors: Mazzeo Salvatore , Lassi Michael , Padiglioni Sonia , Moschini Valentina , Vergani Alberto Arturo , Scarpino Maenia , Giacomucci Giulia , Buralli Rachele , Morinelli Carmen , Fabbiani Carlo , Balestrini Juri , Galdo Giulia , Bagnoli Silvia , Emiliani Filippo , Ingannato Assunta , Nacmias Benedetta , Sorbi Sandro , Grippo Antonello , Mazzoni Alberto , Bessi Valentina
Published: December 2023

Background

Subjective cognitive decline (SCD) represents a target population to be screened for dementia. Previous studies identified demographic, cognitive and generic features associated with higher risk of progression to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We aim to test the accuracy of a machine learning model, trained on features derived from non‐invasive and easily accessible techniques, in predicting conversion from SCD to MCI and AD.

Method

We included 150 SCD patients who underwent neuropsychological examination, assessment of cognitive complaint, mood disorders and cognitive reserve, APOE genotyping at baseline. All the patients underwent clinical‐neuropsychological follow‐up every 12‐24 months for a mean time of 12 years.

Result

During follow‐up, 63 patients were classified as progressive SCD (p‐SCD, 42.0%[95% C.I. = 34.1:49.9], including 41 MCI (27.3% [95%C.I. = 20.2:34.5]) and 22 AD (14.7% [95%C.I. = 9.0:20.3]). 87 patients were classified as non‐progressive SCD (np‐SCD, 58.0% [95%C.I. = 50.1:65.9]). We split the whole sample into a training (80%) and a test group (20%). A gradient boosted trees algorithm was trained on 15 selected features including: age, APOE, education, test assessing for global cognition, immediate and delayed verbal, ecological memory and working memory, language, visuospatial abilities, phonemic fluency and cognitive reserve (Fig.1). This model showed a good accuracy (0.83, AUC = 0.78) in distinguishing p‐SCD and np‐SCD in the test group (Fig.2 and Fig.3).

Conclusion

Our machine learning models might represent a reliable, cost‐effective and globally scalable tool for a first step screening of SCD patients before confirmation of AD pathology via more invasive and expensive tests.
Analysis of lifestyle factors affecting life satisfaction and depression of the super‐aged in South Korea: Using the Korean Longitudinal Study of Aging (KLoSA)
Authors: Kim Ah‐Ram , Lim Young‐Myoung , Lim Seung‐Ju , Park Ji‐Hyuk , Park Kang‐Hyun
Published: December 2023

Background

The purpose of this study was to confirm the correlation between life satisfaction and depression and lifestyle (physical activity, eating habits, frequency of participation, participation diversity) for the super‐aged in South Korea, and to analyze and confirm lifestyle factors that affect life satisfaction and depression.

Method

The independent variables of this study were life satisfaction and depression, and the dependent variables were analyzed including physical activity, regular eating habits, frequency of participation, and diversity of participation as lifestyle factors. For analysis, correlation analysis and multiple regression analysis were performed through SPSS ver 26.0.

Result

As a result of the correlation analysis, it was confirmed that life satisfaction had a quantitative correlation in the order of participation frequency (r = 0.300, p<0.01), participation diversity (r = 0.215, p<0.01), regular eating habits (r = 0.188, p<0.01), and physical activity (r = 0.122, p<0.05). In the case of depression, it was confirmed that there was a quantitative correlation in the order of life satisfaction (r = 0.507, p<0.01), participation frequency (r = 0.297, p<0.01), regular eating habits (r = 0.218, p<0.01), participation diversity (r = 0.128, p<0.05). As a result of multiple regression analysis, participation frequency (t = 6.262, p<0.001) and regular eating habits (t = 4.627, p<0.001) were found to have statistical significance, and participation frequency (t = 6.540, p<0.001), regular eating habits (t = 4.61, p<0.001).

Conclusion

Through this study, lifestyle factors that affect the life satisfaction and depression of the super‐aged in South Korea were identified. Therefore, based on the results of this study, a multi‐faceted intervention program based on lifestyle is needed to improve the life satisfaction and depression of the super‐aged.
Feasibility and safety of a nanoporous system for intrathecal pseudodelivery of anti‐amyloid therapies: proof‐of‐concept in mice
Authors: Szilagyi Andrei , Schreiner Thomas Gabriel , Tomas‐Zapico Cristina , Menendez‐Gonzalez Manuel , Tamba Bogdan Ionel
Published: December 2023

Background

The cerebrospinal (CSF) sink therapeutic strategy hypothesizes that clearing soluble beta‐amyloid from the CSF results in removing brain beta‐amyloid (Aβ) (1). We proposed a new way of achieving the CSF sink effect by means of an innovative route of drug delivery, named intrathecal pseudodelivery (ITPD) of drugs. ITPD is based on an implantable device endowed with semipermeable nanoporous membranes that are permeable to soluble Aβ but not to monoclonal antibodies (mAb) (2). In this study, we aimed to show proof‐of‐concept of a fully implantable device for ITPD in combination with mAbs for selectively clearing Aβ from CSF in a mouse model of Alzheimer’s Disease (AD)

Method

We encapsulated flat alumina nanoporous membranes of a pore size of 10.0 nm, and we coupled the capsule with a reservoir and a catheter. The system was implanted in symptomatic 34‐week‐old male (n = 6) and female (n = 4) APPswe/PS1dE9 mice and their wild‐type littermates (n = 10), with the capsule/reservoir placed subcutaneously and the catheter connected to the right lateral ventricle. Devices were infused with either artificial CSF (aCSF) (n = 10), or an anti‐Aβ mAb solution (n = 10). After surgery, animal welfare and body weight were monitored for up to 30 days. Behavioral tests were carried out before and 30 days after implantation.

Result

Implantation procedure was successful, with a rapid animal recovery period of 15 minutes after the surgery. In 5 of the implanted mice complications related to anesthesia were reported, but none was severe. For the preliminary behavioral analyses, a partial improvement in cognitive functions was evidenced, with no significant adverse effects at any of the time points.

Conclusion

These findings provide proof‐of‐concept on nanoporous systems for ITPD of anti‐Aβ therapies that replicate previous feasibility and safety studies and, together with ongoing studies assessing efficacy, provide further validation of this therapeutic route in AD.
Impact of cognitive stimulation on the autonomy of a patient with early‐onset AD
Authors: Mariani Francesca
Published: December 2023

The relevance of non‐pharmacological cognitive stimulation treatments in patients with MCI and AD is increasingly recognized as tools for slowing the progression of the disease and preserving autonomy. However, the registration and quantification of the impact is diffcult to consign.

The objective of the present work is to present the case of a 59 year old woman, with early onset AD who is undergoing cognitive stimulation treatment and its evolution in cognitive and functional performance.

Initially he presented with typical subjective memory complaint, he obtained a score of 25/30 in MMSE and a CDR of 1. An 18F‐FDG study was performed that showed the typical hypometabolism pattern and a positive 11C‐PIB PET/CT for cortical amyloid deposits. On functionality scales, he scored 100 on the Barthel index and 8 on the Lawton and Brody scale. He underwent cognitive stimulation treatment, from that moment and uninterruptedly, through biweekly sessions of 45‐60 minutes each. It currently has a CDR of 2 and an MMSE of 15/30. In relation to its functionality, it presents a Barthel Index of 100/100 and a Lawton and Brody scale of 4/8.

Although the inevitable progression of the disease has an evident impact on cognitive functions, which is clearly reflected in the neuropsychological tests, the functionality of the patient has been fully maintained for basic activities of daily living, and partially for activities instrumentals. This demonstrates the relevance of personalized cognitive stimulation treatments in patients with Alzheimer’s disease, especially in forms of early presentation, when the disease is more aggressive and when patients are very active at the time of diagnosis.
Sex and APOE differences in Alzheimer’s Disease‐On‐Ramp risk factor profiles: Are all risk factors for Alzheimer’s Disease created equal?
Authors: Merlini Simona , Vitali Francesca , Brinton Roberta Diaz
Published: December 2023

Background

Obesity, diabetes (T2D), hypertension (HTN), cardiovascular disease (CVD), chronic obstructive pulmonary disease (COPD), end‐stage renal disease (ESRD), stroke and hyperlipidemia are known Alzheimer’s Disease (AD)‐on‐ramp risk factors. However, it remains unclear whether the risk conferred by these conditions is modified by other unmodifiable AD risk factors, such as chromosomal female sex and APOE genotype. Therefore, we conducted a retrospective study using the UK Biobank to determine the effect of AD‐on‐ramp risk factors, in combination with sex and APOEε4 carrier status.

Method

UK Biobank dataset consisted of 500k participants. Inclusion criteria were age older than 55 years old, no prior history of neurodegenerative disease, neurosurgery, or cancer, and enrollment with at least 3 years of follow‐up. Patients were propensity score‐matched based on age and educational level. We next conducted stepwise regression analysis to investigate the effect of AD‐on‐ramp risk factors. Sensitivity analyses were computed to evaluate the impact of medications prescribed for the risk factors on AD. Finally, we conducted sensitivity analyses on sex‐specific propensity score‐matched cohorts.

Result

Of the 181,865 participants who met inclusion criteria, 1,503 had AD and were 1:10‐matched to 15,030 patients without AD. In both cohorts, 56% were females and 44% were males and the AD cohort was predominantly APOEε4 carriers (62%). We found that stroke, T2D, HTN, HLP, and ESRD were associated with increased risk of AD, whereas obesity was a protective factor. When controlling by sex and genotype, the effect of APOEε4 was greater if considered with T2D and HTN respectively. Women exhibited greater OR of APOEε4, T2D, and HTN than men, and cholesterol medication protected against AD risk, especially in men.

Conclusion

These findings support previous reports that T2D, HTN, HLP, and ESRD are associated with increased risk of AD. We identified and ranked AD‐on‐ramp risk factors by their impact to explain variation in the AD onset, controlling by sex and genotype. In addition, we found sex‐specific protective factors, where obesity and cholesterol medication were associated with lower risk of developing AD in women and men respectively. Ongoing analyses include evaluation of the age‐dependent effect on AD risk factors, stratified by sex and APOE genotype.
Hyperspectral analysis of amyloid beta (Aβ) evolutional changes in preclinical to late‐stage Alzheimer’s disease using matched brain and retinal tissue
Authors: Flanagan Margaret , Danner Benjamin , Zamudio Carlos , Spencer Callen , Lilek Jaclyn N , Matos Arleen , Morris Meghan , Ajroud Kaouther , Xie Wei , Bornbaum Catherine C , Westreich Jared , More Swati S
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive, degenerative brain disorder that leads to cognitive impairment and eventually death. It is marked by buildup of abnormal amyloid aggregates (Aβ) in the brain. This study aimed to elucidate the neuropathologic sequence and corresponding [RetiSpec] hyperspectral signals of Aβ evolutional changes in preclinical to late‐stage AD using retinal and brain samples.

Method

We used brain‐ and retina‐matched human tissue samples from the NIH Brain Bank at Johns Hopkins. Study groups included: No AD neuropathologic change with negative AD neuropathology (n = 15); Low‐level AD neuropathologic change with positive AD neuropathology (n = 15); High level AD neuropathologic change with positive AD neuropathology (n = 15). To validate retinal hyperspectral imaging (rHSI) detection of Aβ in these retinal samples, we quantified Aβ oligomers (AβOs) in human retinal tissue. Immunohistochemistry was performed. We used humanized, affinity‐matured, IgG2 mAβ selective biotinylated antibody (ACU‐193) to detect soluble AβOs in retinal and brain tissues followed by objective quantification of ACU193 retinal staining by performing annotations and data extraction using QuPath software. One‐way ANOVA and t‐tests were performed to compare between controls and AD stages.

Result

When assessing ACU193 staining present from retinal tissue samples, we observed 29‐53% retinal tissue area positivity in controls and 15‐72% retinal tissue area positivity in the AD group. Level of AD pathology demonstrated an effect on the rHSI spectra (450‐600nm) in regions near the optic disc and the ventral periphery: intermediate AD pathology showed the strongest rHSI signature (decrease in optical transmittance) followed by high, then low AD pathology samples. Correlation of the Braak neurofibrillary tangle stage and ΔOD offered a Pearson r score of 0.79 (p = 0.004).

Conclusion

This study was the first to assess and quantify AβOs in clinically, neuropathologically, and hyperspectrally characterized postmortem matched brain and retinal tissues. Progression of well‐established neuropathologically classified AD stages (e.g Braak) may correlate with retinal AβO levels measured using rHSI. Certain retina regions that share nervous tissue with the brain (optic disc, periphery) are likely more sensitive to rHSI‐mediated detection of AD pathology. Larger samples are needed to comprehensively assess and quantify retinal AβOs.
Incremental declines in independence associated with disease progression in early symptomatic Alzheimer’s disease (AD)
Authors: Chandler Julie , Ye Wenyu , Mi Xiaojuan , Dennehy Ellen B , Atkins Alexandra S , Wessels Alette M
Published: December 2023

Background

Associations between disease progression (DP) and health outcomes are poorly characterized in mild cognitive impairment (MCI) and mild AD (MILD). To address this, we examined the impact of DP on incremental changes in independent functioning over 18 months; baseline factors associated with DP were also explored.

Methods

Participants included amyloid‐positive participants assigned to placebo in EXPEDITION‐1/2/3 (solanezumab) and AMARANTH (lanabecestat) studies. DP defined as worsening ³5 (MCI1) or ³9 (MILD2) points on the Integrated Alzheimer’s Disease Rating Scale (iADRS). Endpoints included proportions of participants requiring home supervision (³1 hour) or unable to leave home independently (score <3) and change in total care partner time. Machine learning methods using penalized logistic regression and random forest identified factors associated with DP. Least squares mean change (LSMC) was estimated from mixed‐model repeated measures.

Results

Of 1884 participants (274 MCI, 1610 MILD), 56% of MCI and 63% of MILD participants met DP criteria over 18 months.

Baseline AD medication use, greater care partner time, worse functional activities questionnaire (FAQ) score and CDR‐SB, higher iADRS, and lower BMI and MMSE increased odds of DP for MILD (Figure 1) but not for MCI.

Proportion of participants with DP requiring home supervision (p<0.001; MILD only) and not leaving home independently (p<0.05; MCI&MILD) increased significantly at each post‐baseline visit over 18 months (Figure 2). DP in MILD only had significantly higher proportions of participants who could not be left home alone or travel outside of home independently vs no DP (p<0.05).

In those with DP, total care partner time increased significantly from baseline to 18 months (LSMC: 46.0±12.5 hours/month for MCI and 73.2±5.5 for MILD) (Figure 3). For DP vs no DP, increased care partner time at 18 months was significantly higher for MILD (LSMC difference, 66.0±9.3 hours/month; p<0.001) but not for MCI.

Conclusions

Early symptomatic AD participants who progressed over 18 months had reduced independence and required more care partner time. Treatments that slow DP may preserve independence and reduce overall health care burden.

References

1. Wessels AM, et al. J Prev Alzheimers Dis. 2015;2:227‐241

2. Wessels AM, et al. J Alzheimers Dis. 2022;88:577‐588.
An ultra‐fast MRI protocol in dementia enabled by Wave‐CAIPI
Authors: Grilo Miguel A Rosa , Chughtai Haroon R , Thomas David L , Cash David M , Beament Millie , Coath William , Prosser Lloyd , Malone Ian B , Lim Emma , Jäger H Rolf , Alexander Daniel C , Fox Nick C , Mummery Catherine J , Parker Geoff JM , Barkhof Frederik
Published: December 2023

Background

Structural brain imaging is essential for the diagnostic workup in dementia and for safety monitoring of disease modifying therapies. MRI has several advantages over other imaging techniques, but its use is limited by cost and availability. Reducing acquisition time holds the potential for its democratisation. We developed a prototype ultra‐fast MRI protocol based on an optimised 3D parallel imaging approach. Here we present the finalised version, developed using a qualitative and quantitative approach to optimisation.

Method

In this ongoing real‐world study, participants are sequentially recruited from the cognitive disorders' clinics of a tertiary centre. Patients due to have a standard 3T MRI scan as part of their diagnostic pathway are eligible. The standard‐of‐care protocol includes T1w, T2w, FLAIR and T2*/SWI sequences [scan time ∼18mins]. The prototype rapid protocol utilises Siemens work‐in‐progress 3D Wave‐CAIPI (Controlled Aliasing in Parallel Imaging) sequences, enabling a reduction in scan time of more than 60% (table 1). For qualitative analysis, scans (of 9 individuals) were reviewed by six raters and assessed side‐by‐side against the gold‐standard scan for diagnostic utility. For a quantitative analysis, volumes were calculated from T1w scans using the default cortical reconstruction and volumetric segmentation pipeline in FreeSurfer 7.3.2. Key volumes (e.g., deep grey matter, cortical grey matter, white matter) for each participant were compared between the two protocols. Independent visual QC was performed on T1w datasets by an experienced clinical trials team.

Result

Side‐by‐side visual assessment results of 9 participants is shown in figure 1. For all sequences bar FLAIR, raters scored the ultra‐fast sequences of comparable image quality in at least 67% of cases. For quantitative analysis, 10 T1w sequence pairs were reviewed, with 1 clinical scan failing QC due to motion. Bland‐Altman analyses (figure 2.) comparing volumes between the clinical and ultra‐fast sequences show little bias.

Conclusion

Our preliminary results demonstrate that for most contrasts the ultra‐fast sequences are diagnostically non‐inferior and quantitatively equivalent to the clinical protocol both for diagnosis and for safety monitoring.
Care practices respecting the autonomy of older people with dementia
Authors: Shimada Chiho , Hirayama Ryo , Ito Mio , Wakui Tomoko
Published: December 2023

Background

How people with dementia perceive the world has been recently described in better detail, making it easier to understand their unique situations and needs. In caregiving situations, it is desirable to understand the subjective world of people with dementia and to consider the impact of the caregiver’s approach. This study aimed to explore how care providers identify cues to understand the needs and subjective world of people with dementia.

Methods

Overall, 4,000 sites (24.3% sampling rate) were selected from all small facilities (with less than 30 residents) providing dementia care in Japan. A questionnaire was mailed to caregiver leaders, and data was collected online. A two‐case vignette depicted a situation in which care staff experienced significant difficulty caring for residents with dementia; one described a resident who refused to bathe and the other a resident who walked around the facility in the middle of the night. In each situation, respondents were asked to speculate on how they would act to understand the thoughts of the person with dementia. The analysis consisted of 1) segmenting and coding the behavioural and verbal descriptions of each scene, and 2) interpreting and categorising the caregivers’ intentions.

Results

There were 599 respondents (response rate 15.0%); of these, 566 and 558 were for the bathing and night‐time situations, respectively. The descripted responses were categorised into the following five groups. 1) Before providing specific care, it is necessary to ‘build a secure relationship’ by spending time together doing activities and talking about unrelated topics, regardless of the care. 2) To understand the resident’s thoughts and feelings, care workers ‘explore the subjective world’ by asking residents directly about their reasons. 3) Care workers also 'infer from objective information' such as care records and other sources. 4) Caregivers should ‘keep trying acceptable methods until the resident agrees to receive care’. 5) Caregivers should ‘allow things to not work out as intended’.

Discussion

The study showed that care providers use a variety of strategies to build rapport and respect the autonomy of the residents, such as exploring, speculating, suggesting, and waiting for the residents to express their intentions.
Designing Homes for Healthy Cognitive Ageing: Passive Sensing of Environmental Quality in the Homes of Older People Living in Scotland
Authors: Quirke Martin , Davison Lisa , Rutherford Alasdair , Bowes Alison
Published: December 2023

Background

Characteristics of the indoor home environment such as temperature, humidity, and air quality are associated with risk of injury, illness, and cognitive decline.

Method

68 passive environment monitoring sensors were installed in the homes of (n = 10) people aged 55 or older, experiencing age related cognitive change, and living in Scotland. The size of the homes ranged from 4‐12 rooms and data collection periods ranged from 2‐7 months. Environment data along with infra‐red based space occupancy data was collected every 60 seconds for the duration of each installation. Analysis included evaluation of sensor based environmental data against participants’ experiential account of their habits and activities whilst living in their homes.

Result

Analyses of average usage patterns, showing typical weekday and weekend activity within the homes over the data collection period were used to identify potential influences on the health supporting qualities of indoor home environments. These include regional weather conditions, occupant activity patterns, ventilation, and heating, as well as the influence of fuel poverty.

Conclusion

High fuel costs in combination with regional climatic conditions may be increasing the risk of indoor home environments contributing to poor health outcomes, including cognitive decline, amongst older people living in Scotland.
Risk of COVID‐19 infection, hospitalization, and mortality in older adults with versus without dementia during the first wave of COVID‐19 pandemic: A Swedish nationwide study
Authors: Hoang Minh Tuan , Wastesson Jonas , Szilcz Máté , Maura Géric , Blotière Pierre‐Olivier , Johnell Kristina
Published: December 2023

Background

The difference in the risk of COVID‐19 infection, hospitalization, and mortality between older adults with and without dementia is understudied. This study aimed to compare the risk of COVID‐19 infection, hospitalization, and mortality between dementia patients aged 65 years and above with non‐dementia counterparts, during the first wave of COVID‐19 in Sweden.

Method

This observational study included data from 2,031,069 older adults in Sweden (2015‐2020), based on the linkage of various Swedish nationwide registries. Outcomes included COVID‐19 infection, hospitalization, and mortality during the first wave of COVID‐19 in Sweden (from 01 March to 31 August 2020). We performed flexible parametric survival models to investigate the association between outcomes and having dementia, adjusted by age at the start of the first COVID‐19 wave in Sweden, sex, Charlson Comorbidity Index, hospital frailty risk score, and other sociodemographic covariates. Subgroup analyses were conducted on age groups, sex and living arrangement (nursing homes versus community dwelling).

Result

Compared to the non‐dementia group (n = 1,965,194), the dementia patients (n = 65,875) were older (median 82.0 years, IQR 77.0‐87.0 versus 74.0 years, IQR 69.0‐79.0), had higher proportions of women (59.1% versus 53.2%), living alone (60.0% vs 47.5%), living in nursing homes (39.0% vs. 2.2%) and having lower socioeconomic positions. Comorbidities were more common among the dementia group, as shown by their higher Charlson Comorbidity Index or hospital frailty risk score. Our main analyses showed the dementia group was at higher risks of COVID‐19 infection (hazard ratio (HR) 3.13, 95% confidence interval (95% CI) 3.00‐3.27), COVID‐19 hospitalization (HR 1.32, 95% CI 1.23‐1.42) and COVID‐19 death (HR 4.01, 95% CI 3.75‐4.29), compared to the non‐dementia group. The dementia group living in nursing homes had higher risks of COVID‐19 infection and death, but a lower likelihood of COVID‐19 hospitalization (HR 0.79, 95% CI 0.68‐0.92), compared to the non‐dementia group.

Conclusion

We confirmed that the older adults with dementia had higher risks of COVID‐19 infection, hospitalization, and mortality, than those without dementia during the first wave of COVID‐19 in Sweden. However, dementia patients living in nursing homes were at a lower risk of COVID‐19 hospitalization, compared to older adults without dementia.
Novel Tip60 HAT activators as neuroepigenetic therapeutic modulators for Alzheimer’s Disease
Authors: Elefant Felice , Bhatnagar Akanksha , Dasari Rohan , Chnogtham Neha , Kortagere Sandhya
Published: December 2023

Background

Alzheimer’s Disease (AD) etiology involves a complex interplay of genetics, age, and environmental factors that influence neuroepigenetic mediated neural gene control. Reduced histone acetylation in the AD brain is a widespread hallmark underlying neural gene repression and cognitive impairment in AD etiology. As histone acetylation is dynamically regulated by antagonistic histone deacetylases (HDACs) and histone acetyltransferases (HATs), pharmacological treatments aiming to restore histone acetylation via HDAC inhibition are a research hotspot for developing AD cognitive enhancing drugs. Although promising, HDAC inhibitor treatments in the AD animal models are rarely translated into clinical trials due to non‐specific global hyperacetylation. Alternatively, enhancing activity of specific HATs with non‐redundant functions serves as an exciting new therapeutic strategy that remains unexplored. To this end, our lab has identified and published a neuroprotective role for HAT Tip60 in multiple neural circuits impaired in AD pathology. Human and Drosophila AD brains exhibit reduced Tip60 and enhanced repressor HDAC2 that triggers histone deacetylation with concomitant repression of cognition genes. All these deficits are prevented by genetically increasing Tip60 in the Drosophila AD brain. Here, we test that pharmacologically enhancing Tip60’s HAT function replicates this AD neuroprotective function.

Method

We used in silico structural modeling and a novel pharmacophore based virtual screening approach to design and synthesize novel small molecule compounds strongly predicted to target and enhance Tip60’s HAT activity.

Result

Our screen produced 19,000 hits that we individually docked on Tip60’s HAT domain using GOLD docking software. 13 compounds were identified that exhibited significantly high Tip60 docking scores, and optimal ease of synthesis, drug like properties and blood brain barrier peneteration. These compounds were custom synthesized. We show that several of these compounds fully rescue locomotor neural based deficits and cognition gene expression alterations in both Tip60 knockdown and AD Drosophila in vivo models with no observable side effects, underscoring their therapeutic effectiveness. These compounds will ultimately be assessed for further specificity and for their therapeutic effectiveness in AD animal models in vivo.

Conclusion

We propose our first‐in‐class small molecule Tip60 HAT activators will serve as powerful novel chemical entities for development of specific acetylation‐based cognition enhancing drugs for AD.
High VEGF‐A and low PlGF in plasma are associated with reduced longitudinal tau PET burden and slower cognitive decline in preclinical Alzheimer’s disease
Authors: Yau Wai‐Ying Wendy , Yang Hyun‐Sik , Carlyle Becky C. , Trombetta Bianca A. , Zhang Can , Schultz Aaron P. , Pruzin Jeremy J. , Fitzpatrick Colleen D , Kirn Dylan , Rabin Jennifer S. , Buckley Rachel F. , Hohman Timothy J. , Rentz Dorene M. , Tanzi Rudolph E. , Johnson Keith A. , Sperling Reisa A. , Arnold Steven E. , Chhatwal Jasmeer P.
Published: December 2023

Background

Vascular dysfunction is increasingly recognized as an important partner in the pathogenesis of Alzheimer’s disease (AD). Alterations in vascular endothelial‐derived growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical AD and their relationships with other AD and vascular pathologies during this critical early period remain to be elucidated.

Method

We examined 316 cognitively unimpaired at baseline older adults from the Harvard Aging Brain Study (Table 1). VEGF family proteins (VEGF‐A, VEGF‐C, VEGF‐D, PlGF, VEGFR‐1) were measured in baseline fasting plasma using MSD V‐PLEX Angiogenesis Panel. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound‐B) on longitudinal cognitive decline (Preclinical Alzheimer Cognitive Composite‐5). We further investigated if effects on cognition may be mediated by longitudinal inferior temporal tau PET burden (Flortaucipir; subset n = 186) or hippocampal atrophy (subset n = 206). Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume (WMH).

Result

High plasma VEGF‐A (β = 0.06, t = 3.23, p = 0.001) and low PlGF (β = ‐0.08, t = ‐3.88, p<0.001) each interacted with elevated baseline amyloid burden to slow prospective cognitive decline (Figure 1A). Concordantly, high VEGF‐A (β = ‐0.12, t = ‐4.56, p<0.001) and low PlGF (β = 0.09, t = 3.63, p<0.001) were associated with reduced longitudinal tau accumulation in those with elevated amyloid (Figure 1B). Moderated mediation analyses revealed that, under elevated amyloid, reduced tau accumulation fully mediated the effects of high VEGF‐A and partially mediated the effects of low PlGF (30%) on slower cognitive decline (Figure 2). There were no significant associations with hippocampal atrophy. The interactive effects of VEGF‐A and PlGF on tau and cognition remained significant after adjusting for cardiovascular risk score or WMH (p<0.003).

Conclusion

High plasma VEGF‐A and low PlGF were associated with slower prospective cognitive decline in preclinical AD, which was fully (VEGF‐A) and partially (PlGF) mediated by reduced tau accumulation. These effects were distinct from conventional vascular risk and injury measures, highlighting VEGF‐A and PlGF as potential molecular targets in preclinical AD to modify the vascular‐AD synergy in combination with anti‐amyloid and traditional vascular risk reduction therapies.
Herpes zoster vaccination prevents or delays dementia: causal evidence from a country‐wide natural experiment in Wales
Authors: Eyting Markus , Xie Min , Hess Simon , Geldsetzer Pascal
Published: December 2023

Background

There is growing recognition that infectious agents, particularly herpesviruses, could play a role in the development of some types of dementia.

Method

In Wales, eligibility for the herpes zoster vaccine (Zostavax) for shingles prevention was determined based on an individual’s exact date of birth. Those born before September‐2‐1933 were ineligible (and remained ineligible for life), while those born on or after September‐2‐1933 were eligible. This natural experiment provides causal, as opposed to correlational, evidence because there is no plausible reason why adults born just one week apart should differ systematically from each other. We used a regression discontinuity design in Welsh country‐wide data on primary and secondary care encounters, and death certificates. The outcome was a new dementia diagnosis as recorded in any of these data sources.

Result

We included 282,541 individuals born between September‐1‐1925 and August‐31‐1941. The percentage who received the zoster vaccine increased from 0.01% among those one week too old to be eligible, to 47.2% among those one week younger. Receiving the vaccine reduced the probability of a new dementia diagnosis over a follow‐up period of seven years by 3.5 percentage points (95% CI: 0.6‐7.1, p = 0.019), corresponding to a 22.4% relative decrease. There were significant protective effects from the vaccine for Alzheimer’s disease but not vascular dementia. Effects were far stronger among women than men. To demonstrate that our approach is causal, we show that i) there were no differences in pre‐existing conditions or uptake of other preventive interventions across the date‐of‐birth eligibility cutoff; ii) the zoster vaccine had no effects on any other common causes of morbidity and mortality; and iii) no other interventions used the same date‐of‐birth eligibility cutoff.

Conclusion

In addition to identifying a readily available preventive intervention for dementia, our findings strongly suggest an important role of the varicella zoster virus in the etiology of dementia, particularly among women. Unlike existing studies in this field, this analysis provides causal evidence because individuals who differ in age by just one week are exchangeable with each other on both observed and unobserved characteristics, except for a large difference in the probability of receiving the zoster vaccine.
Digitized Biomarkers Utilizing Human‐Computer Interaction Sensing Technology for Early Auxiliary Diagnosis of Alzheimer’s Disease
Authors: Luo Benyan
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive and debilitating neurological disorder that impacts millions of individuals globally. Prompt and accurate detection and diagnosis of Alzheimer’s disease are pivotal for providing effective care and management to patients. However, early identification of the disease remains challenging due to the complexity of diagnostic procedures and the similarity of symptoms with age‐related cognitive decline. With the world transitioning towards a more digital‐focused environment, there is an increasing potential to utilize human‐computer interaction technologies to aid in the early detection of Alzheimer’s disease.

Method

We recruited 40 healthy individuals, 40 patients with mild cognitive impairment (MCI), and 40 patients with early AD. By incorporating fusion perception‐enhancing technologies into intelligent identification devices, such as eye‐tracking and body motion detection, peripheral modal biometric information can be gathered from subjects.

Result

The study found that in human‐computer interaction experiments using eye‐tracking, the patients with early AD showed significantly longer completion times and free rates of eye motion and movement trajectory than the normal group and those with MCI. The correlation between eye motion trajectory and movement trajectory was notably lower as compared to the normal group and the MCI group. During the human‐computer interaction physical movement experiment, the AD group recorded lower target accuracy rate and screen click rate as compared to the normal group and patients with MCI. Similarly, in the human‐computer interaction clock drawing experiment, the AD group demonstrated longer completion time and pen‐up thinking time, as well as lower clock drawing scores. Furthermore, the total completion time of human‐computer interaction tasks was notably shorter as compared to conventional cognitive screening tests. In conclusion, peripheral biomarkers obtained from the aforementioned human‐computer interaction task were analyzed using machine learning techniques, resulting in the identification of early‐stage Alzheimer’s disease with a classification accuracy of 91.1%.

Conclusion

Hence, this non‐invasive and accurate technique may prove instrumental in identifying potential cognitive deficits associated with this disease while also being widely applicable for screening early AD.
Informed consent process experience in Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease Colombia trial
Authors: Ríos‐Romenets Silvia , Giraldo‐Chica Margarita M. , Gutierrez Madelyn , Acosta‐Baena Natalia , Espinosa Alejandro , Quiroz Yakeel T. , Ruiz Alejandra , Giraldo Andrea , Langbaum Jessica B. , Cho William , Reiman Eric M. , Tariot Pierre N. , Lopera Francisco
Published: December 2023

Background

Recruiting cognitively‐unimpaired volunteers at high genetic risk of developing dementia into the Alzheimer’s Prevention Initiative (API) Colombia trial, and maintaining study adherence for at least 5 years has been a monumental challenge. Major barriers included inclusion criteria, protocol visit schedule, long informed consent form (ICF), low levels of education of participants, misconceptions about participating in a clinical trial, and blinding to genetic status and treatment arm. We explain how our group went out of the conventional and traditional schemes of informed consent while adhering to good clinical practice and developed a novel approach to the consent process for potential candidates.

Method

The identification, community education, and follow‐up of affected PSEN1 E280A families for the past three decades was the initial fundamental step to initiate a proper ICF process for the study. Then the launch of API Colombia Registry in 2010 was the base for appropriate preparation for the prevention trial. The process for API Colombia trial included step by step strategies, such as: a pre‐screening process developed by the team, pre‐consent informational meeting with the principal investigator in small groups of potential candidates, illustrated materials like a booklet titled “What I should know about informed consent and my decision to participate”, and detailed infographics as a complementary material to main study ICF, use of a voluntary pre‐selection survey. The screening visit was divided in parts: discussion with the sub‐investigator about clinical trial participation, review of participant’s questions, and signatures according to regulatory requirements.

Result

From 623 potentially eligible registrants for pre‐screening, 319 were consented and underwent full eligibility screening and 252 were randomized. After eight years of study duration, 94% of participants completed the protocol, 90.5% completed the trial on treatment. Most participants who dropped out of the study did it due to incompatibility with work, unexpected pregnancy, or the decision to have children.

Conclusion

We attribute successful trial adherence to the consent process that led to a well‐informed, voluntary, and responsible decision, and the participant’s understanding of the unique contribution they can make to change the world by participating in clinical research.
Exploring treatment guidelines for amyloid therapies in Alzheimer’s Disease Using Predictive Quantitative System Pharmacology Modeling
Authors: Geerts Hugo , Bergeler Silke , Walker Mike , Rose Rachel , Van der Graaf Piet
Published: December 2023

The recent approvals of amyloid antibodies for treatment of Alzheimer’s disease have heralded a new era in the physician’s treatment toolbox and the availability of individualized treatment guidelines for patients will greatly benefit an ever greater patient population. However, generating these guidelines using clinical experiments is not feasible.

We used a mechanism‐based Quantitative Systems Pharmacology model, well validated with published natural history and group average clinical trial data of six amyloid antibodies and applied it to individual scenarios, including APOE genotype. For baseline SUVR between 70 and 180 centiloids, the time to reach amyloid negativity was predicted to range on average from 25 to 64 months for aducanumab, 18 to 47 months for lecanemab and 10 to 25 months for donanemab. Interestingly, we derived a relationship between the baseline SUVR load and the changes in plasma Ab42/Ab40 ratio or CSF Ab42 level associated with reaching amyloid negativity. This relationship is different for each antibody with lecanemab more sensitive than donanemab and aducanemab and provides an alternative to PET imaging to determine the time of reaching amyloid negativity. ARIA‐E liability for an APOE4 carrier ranges between 20 and 31% for aducanumab, 10‐18% for lecanamab and 17‐27% for donanemab during the time to reach Abeta negativity.

After reaching amyloid negativity, stabilization over 10 years follow‐up can be achieved with a 32‐fold reduction in exposure for all three antibodies, either with a lower dose, lower frequency or a combination of both.

For patients with a three‐month dose holiday after an ARIA‐E incident, the delay in reaching amyloid negativity is predicted to range from 3 to 6 months for aducanumab, 2 to 4 months for lecanemab and 1.7 to 3 months for donanemab, depending on the titration schedule after reinstatement of the treatment.

Finally, after implementation of the trisomy 21 effect, we explored optimal trial designs for autosomal dominant Down syndrome patients for each of the three antibodies.

This simulation can be applied to any newly approved drug given the pharmacology (affinities against different Abeta peptides) and PK profile and many individual case scenarios.
Therapeutic effects of blood‐brain barrier opening with low‐intensity pulsed ultrasounds in tau transgenic P301S mice
Authors: Géraudie Amandine , Riche Maximilien , Lestra Thaïs , Carpentier Alexandre , Delatour Benoit
Published: December 2023

Background

Alzheimer’s disease is the most frequent cause of dementia. To date, almost no disease‐modifying therapeutics have proven clinical efficacy. Most of these therapeutics have targeted amyloidosis whereas tau pathology is better correlated to cognitive decline. Moreover, drugs have difficulty crossing the blood‐brain barrier (BBB) which drastically restricts their penetration into the brain parenchyma. It has been previously shown that the BBB can be safely, transiently and repeatedly opened using low‐intensity pulsed ultrasound along with microbubbles (LIPU‐MB, sonication). BBB opening with LIPU‐MB alone provides beneficial effects on amyloid burden, increase neurogenesis and modulate neuroinflammation. Our study aims at evaluating the effect of LIPU‐MB BBB opening in P301S mice model of tauopathy on tau pathology. Its secondary aims are to evaluate the effects of LIPU‐MB BBB opening on neuroinflammation, synapse density and neurogenesis.

Methods

Five sessions (one per week) of LIPU‐MB were administered to wild‐type and P301S mice. Mice were sacrificed one week after the last session. Immunostaining of phosphorylated tau (AT8), microglia (Iba‐1), synapse (synaptophysin) and neurogenesis (doublecortin) were compared between the sonicated and non‐sonicated groups.

Results

There was a global trend for an increase of phosphorylated tau, significant in the piriform cortex, in sonicated P301S male mice (p<.05). Interestingly, microglial densities were decreased in all brain areas in these mice (p<.0001) whereas they were increased in wild‐type mice. Tau pathology and microglial density differences between sonicated and non‐sonicated animals did not appear anymore in P301S female mice. Synapse density and neurogenesis in the hippocampus did not appear to be affected by sonication in P301S mice.

Conclusion

Our results show that LIPU‐MB BBB opening decreases microglial cells loads in P301S male mice and concomitantly may impact tangles pathology. They also underline that the effects of transient BBB opening may be both sex‐ and genotype‐dependent. These results could have therapeutical impact for Alzheimer’s disease but need to be confirmed in larger cohorts of mice.