bluuebunny/crossref_metadata_2025 huggingface dataset:
Leveraging videoconferencing supports the continuity of Alzheimer research during the COVID‐19 pandemic and beyond
Authors: Johnson Francelethia S , Lacroix Faina C , Contreras Maricarmen , Baez Penelope , Ayodele Temitope , Martinez Izri , Fonseca Sandra , Adams Larry D , Welch Jacob , Jean‐Francois Melissa N , Mena Pedro Ramon , Reitz Christiane , Vance Jeffery M , Pericak‐Vance Margaret A , Cuccaro Michael L , Beecham Gary W
Published: December 2021

Background

The COVID‐19 pandemic has placed a demand on researchers to limit in‐person contact with participants, greatly impacting Alzheimer Disease (AD) research. To address this problem, we describe here an approach to using digital technology to continue nationwide clinical recruitment and ascertainment of biological samples while adhering to COVID‐19 guidelines and travel restrictions.

Method

To accomplish this, we considered a videoconferencing approach for remote delivery of cognitive assessments. A multi‐site panel of neurologists and clinical psychologists and a detailed literature review ensured a protocol that captures the best‐practices for administering assessments through videoconferencing while ensuring consistency between remote and in‐person administration. Clinical coordinators underwent training to ensure good agreement with in‐person administration. Most aspects of the cognitive assessments easily transferred to videoconferencing, though Trail Making A and B, and Digit Symbol‐Coding were removed to protect the integrity of the evaluation. Additionally, we coordinated the collection of biological samples with a national company, Quest Diagnostics, to provide phlebotomy services at the participant’s residence. All protocols were developed under the guidance of the Human Subjects Research Office at the University of Miami and with approval of local IRB.

Result

Our clinical coordinators completed over two dozen remote assessments using these protocols. Both cases and controls were enrolled, across various ethnic populations within our study. The distributions of age and 3MS were similar between in‐person and remote assessments. The uptake of videoconferencing enrollment varied among the age groups, level of impairment, at‐home support system and telemedicine readiness. For example, earlier‐onset groups had the best uptake, while older‐onset groups showed the least uptake due to a higher prevalence of telemedicine unreadiness (Lam et al., 2020; Bossen et al.,2015).

Conclusion

This study demonstrates that remote enrollment and ascertainment of biological samples through videoconferencing and partnering with national mobile phlebotomy services is feasible. This approach allows researchers to continue ascertainment efforts while maintaining their participants’ autonomy through informed consent and privacy throughout the process and minimizing their exposure to COVID‐19.
Heterogeneous associations of air quality improvement with domain‐specific cognitive function in older women
Authors: Wang Xinhui , Younan Diana , Petkus Andrew J , Beavers Daniel P , Espeland Mark A , Millstein Joshua , Chui Helena C , Gatz Margaret , Chen Jiu‐Chiuan
Published: December 2021

Background

Air pollution is associated with increased risk of cognitive decline and dementia. However, whether and how air quality (AQ) improvement is associated with better cognitive performance across multiple domains is unknown.

Method

Participants included 2,114 women (aged 74‐92 at the enrollment) from the US‐based Women’s Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes. Cognitive domains evaluated annually included episodic memory (EM; sum of scores by immediate and delayed recalls of East Boston Memory Test and the word list of modified Telephone Interview for Cognitive Status), language (Verbal Fluency‐Animals), working memory (WM, sum of scores from forward and backward Digit Span Tests), and attention/executive function (AEF, log‐transformed ratio of the time spent in Part A over Part B for Oral Trails Making Test), all standardized using corresponding baseline measure. Annual PM2.5 (fine particulate matter) and NO2 were estimated using regionalized universal kriging models and aggregated to 3‐year average at 10 years (remote) and immediately (recent) before enrollment. AQ improvement was defined as reduction from remote to recent exposures. We examined associations between AQ improvement and domain‐specific cognitive trajectories using linear mixed effect models, adjusting for sociodemographic, lifestyle, clinical covariates, and time‐varying propensity scores to account for selective attrition.

Results

AQ improved significantly over 10 years for both PM2.5 (13.3±2.7µg/m3 to 10.6±2.0µg/m3) and NO2 (15.7±7.1ppb to 10.4±4.9ppb). Over a median of 6.2 (inter‐quartile‐range [IQR]=5.1) years of follow‐up, cognitive performance declined significantly in all domains. Women residing in locations with greater PM2.5 improvement (per IQR=1.77µg/m3) had better performance in EM (βPM2.5=0.069, p=0.002), WM (βPM2.5=0.050, p=0.01), and AEF (βPM2.5=0.044, p=0.01), but not in language (βPM2.5=0.013, p=0.57). Similar findings with stronger associations were observed with improved NO2 (βNO2=0.065∼0.073 per IQR=3.89ppb for EM, WM and AEF, all p≤0.002). Slower declines in cognitive trajectories across EM, Language and AEF were found with improved AQ, but only the association between improved NO2 and slower EM decline was statistically significant (βNO2=0.010/year, p<0.001).

Conclusions

Improved AQ of PM2.5 and NO2 was associated with better performance of EM, WM and AEF, but not language. In addition, improved NO2 was associated with slower decline of EM over time in older women.
Associations between neutrophils and amyloid deposition in the Alzheimer’s disease spectrum
Authors: Rahmouni Nesrine , Tissot Cécile , Lussier Firoza Z , Bezgin Gleb , Therriault Joseph , Stevenson Jenna , Stevenson Alyssa , Chamoun Mira , Kang Min Su , Pascoal Tharick A. , Gauthier Serge , Benedet Andréa Lessa , Rosa‐Neto Pedro
Published: December 2021

Background

Neutrophils are key components of early innate immunity and contribute to uncontrolled systemic inflammation. Several studies have highlighted the link between systemic inflammation and the Alzheimer’s disease (AD) pathophysiology. In fact, experiments with animal models and studies with AD patients demonstrated the hyperactivation of neutrophils associated with AD pathology and cognitive decline. However, the comprehension of the inflammatory component in the AD spectrum is still uncomplete. We thus investigated whether the amount of systemic neutrophils is correlated with brain amyloid‐β in the AD spectrum

Method

The present study was conducted in a population of 170 individuals (115 cognitively unimpaired (CU) and 55 cognitively impaired (CI; 35 MCI and 20 AD) from the Translational Biomarkers in Aging and Dementia TRIAD cohort. The neutrophil relative values were assessed using the Automated Beckman DXH hematology Analyzer. Amyloid (Aβ) deposition was assessed with [18F]AZD4694 PET. A voxel‐based regression model evaluated the relationship between neutrophil count and Aβ PET, adjusted for age, sex, years of education and diagnosis. RFT was used to account for multiple comparisons.

Result

In the present study, a positive association was found between systemic neutrophil counts and brain Aβ load, where the associated regions were the anterior cingulate, cuneus, and occipital pole areas. Also, CI individuals showed significantly higher neutrophil counts as compared to the CU group.

Conclusion

Our findings review the link between the peripheral immune system and the central nervous system amyloid deposition. Further studies should investigate the use of neutrophil counts as biomarkers of AD.
The WW‐FINGERS‐SARS‐CoV2 initiative: Impact of the COVID‐19 pandemic on brain health and prevention strategies
Authors: Mangialasche Francesca , Pérez Kristal Morales , Lehtisalo Jenni , Solomon Alina , Peltonen Markku , Ngandu Tiia , Kivipelto Miia
Published: December 2021

Background

Older adults have higher risk of cognitive impairment and dementia, and they also represent the group most severely affected by the SARS‐CoV‐2 (COVID‐19) pandemic in terms of higher morbidity and mortality. The World‐Wide FINGERS (WW‐FINGERS) global network of multidomain trials for dementia risk reduction and prevention (Kivipelto et al., 2020) provides a unique framework to explore how the pandemic has affected factors related to mental and physical health of populations at increased risk of dementia, while accounting also for country‐specific strategies to contain the spread of the infection.

Methods

The WW‐FINGERS‐SARS‐CoV2 survey has been developed to explore direct and indirect effects of the pandemic in midlife and older age. The questions aim to measure changes in lifestyle factors (e.g., diet, physical activity), management of chronic noncommunicable diseases (e.g., diabetes, hypertension), as well as psychosocial factors ‐ including depressive symptoms, sleep disorders, social isolation ‐ that are relevant to cognition and are expected to be affected by the pandemic. The survey measures also established and possible epidemiologic risk factors for severe COVID‐19. To facilitate distribution is different settings, both a pen‐and‐paper and a digital version of the survey have been developed in several languages. The digital version is supported through REDCap (Research Electronic Data Capture), a secure web‐based software that is being also used for harmonized data collection.

Results

Over 25 countries are taking part in the survey. Local adaptations and piloting are being done to optimize implementation in both clinical‐based and population‐based settings. Participants are in the at‐risk spectrum for dementia: from cognitively normal persons to individuals with pre‐dementia cognitive symptoms. An updated report of the survey status will be presented.

Conclusion

the survey is a joint global action of the WW‐FINGERS network which can inform better care of older adults in the context of a pandemic. The survey is also a valuable tool for pre‐screening of participants for prevention trials, and results can inform adaptions to ensure successful recruitment and adherence in forthcoming multidomain trials for dementia prevention in older adults.
The association between visual discrimination and cognitive decline prior to clinical diagnosis
Authors: Jiang Lydia , Shing Nathanael , Robin Jessica , Ladyka‐Wojcik Natalia , Choi Anika , Ryan Jennifer D , Barense Morgan D , Olsen Rosanna K
Published: December 2021

Background

The development of dependable screening methods would allow for the early detection of incipient Alzheimer's disease (AD). Alzheimer’s pathology accumulates in the perirhinal cortex (PRC) well before diagnosis. Converging lines of research show the PRC critically contributes to object visual processing, especially when disambiguating between objects that have highly overlapping features (Barense et al., 2010; Bussey et al., 2002). Previous research has shown that healthy older adults with a genetic risk (i.e., family history) for AD, performed worse at discriminating novel objects than those without a genetic risk (Mason et al., 2017). A dependable screening method, such as a visual discrimination task, could help identify cognitive decline earlier than a typical screening tool.

Method

Twenty‐nine healthy older adults were tested on a visual discrimination task and were also administered the Montreal Cognitive Assessment (MoCA). Based on their MoCA scores, the participants were divided into an “at‐risk” group (n=13) and a “healthy” group (n=16). Each trial consisted of the simultaneous presentation of three visually similar images. Participants were instructed to identify the image that was inconsistent with the other two as quickly and accurately as possible. Images were divided into three categories: faces, scenes, and objects.

Result

The at‐risk group scored significantly lower on the visual discrimination task when compared to the healthy group (p = 0.004). Further, there was a significant interaction between visual image category and MoCA performance on accuracy. This interaction was due to the large difference in accuracy between the two groups in the object category (p < 0.001). Finally, the category had a significant effect on accuracy, where both groups scored significantly lower in the object category (p < 0.001).

Conclusion

This study shows participants who are at‐risk for mild cognitive impairment performed significantly worse on the visual discrimination task especially in the object condition, which is consistent with previous results in healthy older adults with a genetic risk of AD. Impaired visual discrimination could reflect very early AD pathology affecting the PRC. Visual discrimination tests could be developed into dependable screening tools allowing clinicians to make earlier predictions about who is most at risk for developing AD.
Calsyntenin‐1 is a cerebrospinal fluid marker of frontotemporal dementia‐related synapse degeneration
Authors: Belbin Olivia , Irwin David J. , Alcolea Daniel , Illán‐Gala Ignacio , Santos‐Santos Miguel A , McMillan Corey T. , Dolcet Sonia Sirisi , Dols‐Icardo Oriol , Cervantes‐González Alba , Querol‐Vilaseca Marta , Blesa Rafael , Fortea Juan , Lee Eddie B. , Trojanowski John Q. , Grossman Murray , Lleó Alberto
Published: December 2021

Background

Frontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD), a surrogate marker of synapse loss could aid the early diagnosis of FTD. The aim of this study was to evaluate the diagnostic performance of a panel of 9 synaptic proteins in cerebrospinal fluid (CSF) for FTLD in a neuropathological cohort.

Method

We included cognitively normal controls (n=35, 69 years+/‐7) and patients with neuropathological confirmation of FTLD (n=49, mean age‐at‐CSF 67 years+/‐10) or AD (n=25, 73 years+/‐6) from the Penn FTD Center. Subsets of the FTLD group included FTLD‐TDP (n=25) and FTLD‐Tau (n=24) neuropathological subtypes and “pure FTLD” (neurofibrillary tangle score of B0/B1 according to the NIA‐AA classification; n=39). We quantified the synaptic panel by targeted mass spectrometry using isotopically‐labeled proteotypic peptides as internal standards. We used linear regression with Dunnett’s post‐hoc tests to compare group differences, receiver‐operating characteristic curves to assess diagnostic accuracy (AUC) and linear regression adjusting for age‐at‐death and sex to assess the association with tau burden.

Result

Of the 9 synaptic proteins, CSF Calsyntenin‐1 showed the strongest association with disease etiology (r2
=.12, p=.0006). Calsyntenin‐1 was lower in FTLD compared to controls (p=.03) and AD (p=.0008), particularly in “pure FTLD” (p=.02 vs controls, p=.0004 vs AD). Calsyntenin‐1 levels were comparable between AD and controls (p=.33) and between neuropathological FTLD subtypes (p=.66). Calsyntenin‐1 did not correlate with age‐at‐CSF analysis in controls (p=.74), FTLD (p=.07) or AD (p=.40). Calsyntenin‐1 showed the best diagnostic accuracy for differentiating FTLD from AD (AUC=73.4%) and showed similar accuracy in “pure FTLD” (AUC=75.7%) and in FTLD‐TDP (AUC=76.0%) and FTLD‐Tau (AUC=70.4%). Calsyntenin‐1 directly correlated with global pathological tau burden in FTLD (r2=.22; p=0.005) and in “pure FTLD” (r2=.17; p=0.02).

Conclusion

Low CSF levels of the post‐synaptic modulator, Calsyntenin‐1, is specific to FTLD, particularly in cases with little or no tau pathology and could aid the early diagnosis of FTD and the differential diagnosis from AD and other tauopathies.
A systematic review of the use of play in dementia care
Authors: Li Bingyu , Luo Yinglin , Lin Mulin
Published: December 2021

Background

Some psychosocial intervention such as stimulation‐oriented approaches including group play programs are being regarded as helpful intervention approach for old adults with dementia. Many scholars have been talking about the effectiveness of group play programs for elder adults to impair their cognitions and improve the quality of the patient’s life.

Aim

To systematically review the evidence regarding the efficacy of game orientated group play approaches in dementia care.

Method

Literatures are reviewed from several databases including OVID MEDLINE, PSYCHINFO, EMBASE, and Google Advanced Search with pre‐specified selection criteria, elder with dementia (EWD) are participants and interpersonal group play are the mode of intervention.

Result

15 studies met the inclusion criteria (8 randomized controlled trials, 2 observation studies and 5 qualitative studies). Play interventions included individual game and group play. Although studies were generally underpowered, findings indicated positive effects of play interventions on emotional stability, cognitive functioning and general quality of life of people living with dementia.

Conclusion and Implication

As a mode of intervention, group play can effectively improve cognitive functions and psychological symptoms of EWD, and culturally tailored programmes format may further enhance their effectiveness.

Limitation

Game‐based intervention largely lack theoretical frameworks and empirical evaluation; The dynamic process in game‐based intervention between service providers and service users are not being studied.
Geographic proximity, neuropathology and ADRC brain donation
Authors: Powell W Ryan , Zuelsdorff Megan , Chin Nathaniel A , Buckingham William R , Rissman Robert A , Bendlin Barbara B , Kind Amy J
Published: December 2021

Background

Diverse representation is a known challenge in Alzheimer’s disease research recruitment. Geographic proximity to an Alzheimer’s Disease Research Center (ADRC) may be a factor in brain donation. Whether those donating living closer to a center differ in terms of their social and biological characteristics to those living farther away is unknown.

Methods

In this cross sectional analysis of people donating to one of two ADRC brain banks (n=428), we examined how geographic proximity to the center, defined as living within an hour of the center, is associated with neighborhood disadvantage (Area Deprivation Index rank) as well as neuropathology at the time of death.

Results

Disadvantaged neighborhoods were underrepresented regardless of location. However, those living in disadvantaged neighborhoods nearest to an Alzheimer center were less likely to donate than those living farther away. With each decile increase, denoting higher levels of neighborhood disadvantage, the odds of living within an hour of a center decreased by 33% (OR=0.75, 95% CI=0.62‐0.91). Similar trends were found with Alzheimer’s disease‐related neuropathology, with a lower odds of living near a center associated with increasing Braak staging (B score) for neurofibrillary degeneration (OR=0.68, 95% CI, 0.59‐0.77), amyloid plaque presence (OR=0.73, 95% CI, 0.62‐0.87), and presence of Lewy bodies (OR=0.54, 95% CI, 0.40‐0.73).

Conclusion

Findings suggest donation program recruitment approaches could be optimized in disadvantaged neighborhoods, including those geographically closest to centers. Reducing Alzheimer disparities and generating the evidence needed to promote brain health for everyone requires diverse research representation, including areas near an ADRC. ADRC policy and planning efforts that facilitate research access, broaden inclusivity, and expand participation to those living in disadvantaged neighborhoods are needed.
Monthly mortality from Alzheimer’s disease and other dementia in Japan
Authors: Kanamori Masao , Suzuki Mizue , Kanamori Takuya , Naito Tomoyoshi
Published: December 2021

Background

The aim of this study is to research seasonal changes in dementia mortality in Japan and to pursue the excess death on COVID‐19. COVID‐19 excess mortality were higher in homes providing nursing services to older people with dementia in England by Marciano, 2021. We have been researched the temperature‐mortality associations. The optimum temperature with the lowest mortality rate is the 84th percentile of the maximum temperature. We compared the changes in monthly mortality between 2019 and 2020, and examined whether there is an indirect effect on dementia associated with COVID‐19, considering the effects of temperature so far. For comparison, the total deaths of the elderly and accidental deaths such as falls were used.

Method

From the monthly death from dementia (G30, Alzheimer disease, F01‐03, Vascular Dementia and Other) extracted from the vital statistics in Japan from 2019 to 2020, the dementia mortality rate by sex‐age group aged 65 and over was obtained. We estimated excess mortality using estimates from the optimal curves of monthly temperatures and monthly mortality rates for NCD since 2001, which the author has already announced.

Result

Seasonal changes in dementia in 2019‐2020 were assessed to be consistent with estimates from optimal curves for monthly temperature and mortality. However, the 2020 mortality by gender‐age‐class based on 2019 increased sharply in June, August and October for ages 65‐69 and in October (10.2‐43.8 percent) for ages 70‐74. From May to August, falls and traffic accidents decreased, the total mortality of the elderly excluding accidents decreased during the same period, and the mortality of aged 70 and over increased by 8 percent after October. Discussion: The effect of COVID‐19 on dementia in 2020 could not be detected. Since the number of clusters of geriatric medical facilities in Japan has increased significantly since January 2021, long‐term inactivity of physical activity as a factor of immune function decline may increase the mortality from dementia. There are limits based on vital statistics.

Conclusion

Excess mortality from Dementia was undetectable in 2020, but an increased mortality was observed in certain age groups after the autumn.
Reliability and validity of the decision‐making scale on person with dementia
Authors: Suzuki Mizue , Asai Yatami , Sato Masako , Tsujimura Shouko , Koide Yukio , Ogawa Asao , Kanamori Takuya , Naito Tomoyoshi , Inagaki Keigo , Kanamori Masao
Published: December 2021

Background

Recently, the decision‐making for patients is crucial. However, for person with dementia(PwD), it is often the family that decides the treatment. The study aims to develop a decision‐making support scale to determine concrete communications or support methods for PwD.

Methods

A questionnaire survey was conducted among care staff in geriatric facilities from February–March 2021.

Results

Total subjects were 138 persons, with 91 caregivers being the most common. Two scales were developed using factor analysis and Covariance Structure Analysis. The first is a decision‐making scale concerning PwD’s everyday life. The second decision‐making scale pertains to the final stages of the lives. The decision‐making scale on their everyday lives consisted of three factors. The first factor was called the formation and expression of PwD’s wish in their everyday life. The second factor was called the creation of attitudes relating to the formation and expression of wishes of PwD in their everyday lives. The third factor was called the formation of support for the realization of the wishes in their everyday lives. Similarly, the decision‐making support scale on the final stages also had three factors. The first was called support and cooperation among families and multi‐factorial staff in realizing the wishes of PwD during the final stages of their lives. The second factor was called the creation of communication for the formation and expression of the wishes of PwD on the final stages of their lives. Lastly, the third factor support abilities of decision‐making and sense of values in drawing wishes. These scales had a significant relation with attitude scale of decision‐making.

Conclusion

The decision‐making support scales have validity and reliability for PwD from everyday life to the final stages.
Investigating the prevalence of cognitive impairment in mild and moderate COVID‐19 patients two months post‐discharge: Associations with physical fitness and respiratory function
Authors: Vavougios George D. , Stavrou Vasileios , Papayianni Eirini , Fradelos Evangelos C , Astara Kyriaki , Tourlakopoulos Konstantinos , Boutlas Stylianos , Gourgoulianis Konstantinos
Published: December 2021

Background

The aim of our study was to investigate the prevalence and associations of cognitive impairment in previously COVID‐19 patients 2 months after discharge.

Method

Our study included previously hospitalized, consecutive COVID‐19 patients with mild to moderate disease, followed up 2 months post discharge at a tertiary hospital’s outpatient clinic during May 2021. Exclusion criteria included intensive care unit admission, intubation, or a history of neurodegenerative disease and stroke prior to COVID‐19. Prior to inclusion, eligible patients had provided written informed consent. The full battery of measurements in our study included demographics, medical and family history, anthropometrics, the 6‐minute walk test (6MWT), the Borg Dyspnea Scale, spirometry, the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Short Form 36 health Survey (SF‐36), the Montreal Cognitive Assessment (MoCA) and the Symptom Checklist 90‐R (SLC90‐R), reactive oxygen metabolites (dROMs) and plasma antioxidant capacity (PAT test; FRAS5, Parma, Italy). Cognitive impairment was considered on a MoCA cutoff ≤24. Data are presented as mean ±SD or Frequencies (%). Correlations between continuous data were assessed via the Spearman’s Rho correlation coefficient, whereas associations were assessed via multiple linear regression (MLR) models. For all tests, a p‐value <0.05 was considered statistically significant.

Results

A total of 32 subjects were included in the study (35 Male, 17 Female; Mean age of 61.6±9.4). A total of 56.2% presented with cognitive decline (CD) as indicated by a MoCA score <24. Principal component analysis revealed that short‐term memory impairments and multidomain impairment without short‐term memory deficits were the predominant patterns of cognitive impairment. MoCA score correlated with age (ρ=‐0.513, p=0.003), waist circumference (ρ=‐0.388, p=0.028) waist to hip ratio (ρ=‐0.361, p=0.042) and SpO2 during 6MWT (1st, 4th and 6th minute; p<0.05). MLR indicated that after adjusting for age and gender, SpO2 at the 6th minute of the 6MWT was independently associated with MoCA score (Beta=0.579, p‐value=0.001).

Conclusion

Our findings indicated that among 32 outpatient clinic subjects, 56.2% presented with cognitive decline. The associations with oxygen saturation and physical condition as detected by the 6MWT may indicate overlap with post‐COVID‐19 fatigue and warrants further investigation.
PRX012 induces microglia‐mediated clearance of pyroglutamate‐modified Aβ in Alzheimer’s Disease brain tissue
Authors: Tam Stephen , Zhang Gang , Li Lauri , Elmaarouf Abderrahman , Skov Michael , Dolan Philip , Kinney Gene G , Campbell Brian , Zago Wagner M
Published: December 2021

Background

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder featuring hallmark Aβ plaques that spread throughout the brain as the disease progresses. Removal of these plaques has been a focal point of research toward developing treatments for AD, and outcomes from multiple development programs support the prediction that monoclonal antibodies (mAbs) that reduce Aβ plaques meaningfully slow clinical decline in AD patients (e.g., aducanumab, donanemab, lecanemab). Donanemab, which specifically targets pyroglutamate‐modified Aβ, was recently reported to reduce Alzheimer’s‐related cognitive decline in a phase 2 clinical trial. PRX012 is a high‐potency IgG1 mAb targeting the N‐terminus of Aβ with ∼70pM affinity (KD) for Aβ fibrils. In the current study, we assessed whether PRX012, an N‐terminal Aβ targeting IgG1 antibody, stimulates microglial‐mediated clearance of Aβ species, including pyroglutamate‐modified Aβ (AβpE3‐42), in amyloid plaque‐bearing AD brain tissue.

Method

The impact of PRX012, and other Prothena N‐terminal anti‐Aβ antibodies, on microglia‐mediated phagocytic clearance of Aβ plaque species was assessed ex vivo using cryostat sections of human AD brain. Test antibodies or isotype control were applied to plaque‐bearing AD tissue samples, which were then incubated with murine microglia for 72 hours. Determination of total Aβ (Aβ1‐42) and AβpE3‐42 levels were assessed by enhanced chemiluminescent detection and ELISA.

Result

PRX012 and other Prothena N‐terminal anti‐Aβ antibodies promoted rapid and robust microglia‐mediated clearance of Aβ species associated with plaques in human AD tissue. Compared to isotype control, PRX012 significantly reduced both Aβ1‐42 levels as well as pyroglutamate‐modified Aβ species.

Conclusion

PRX012, an N‐terminal‐targeted anti‐Aβ antibody, facilitated abundant microglia‐mediated clearance of Aβ plaque species, including pyroglutamate‐modified Aβ, in brain tissue from AD patients. These data support further development of PRX012 as a potential subcutaneous next‐generation, best‐in‐class Aβ immunotherapy for AD.
Concerns of older adults during second COVID wave in India
Authors: Chopra Meenakshi , Dasgupta Jayashree
Published: December 2021

Background

A second wave of COVID infections in India, lockdown, restriction on services, and strain on an unprepared health system has had significant impact on older adults. It is important to examine impact of the lockdown on the elderly and their caregivers, useful coping strategies and requirements for support going forwards.

Method

As part of an ongoing community engagement initiative with older adults, an online survey was conducted in 2020 during the first wave of the pandemic investigating mental health and wellbeing of older adults. Participants who shared details were contacted one year later to understand impact of the second COIVD wave on their wellbeing and coping. An in‐depth telephonic interview was conducted and General Health Questionnaire 5 item were used for data collection. Audio consent was taken prior to interviews which were recorded and transcribed for thematic analysis.

Result

Out of 58 participants who shared contact details, 16 % (N=9) agreed to participate in the interview. about 40 % refused mentioning they were unwell/ too busy/or agreed to speak at a later date. One female and 8 males participated in the interview between the ages of 36 to 83 years. All participants held post graduate/ professional degrees. 33 % (N=3) participants obtained a GHQ score of 2 and above on the five item General Health Questionnaire indicating presence of depressive features. As compared to the first lockdown, older adults found the second lockdown more stressful due to deaths of close friends and family members. Increased fears about family members with comorbidities contracting the virus, difficulties managing emotional wellbeing, and challenges helping younger family members manage their routines and follow basic COVID protocols were key concerns. Coping strategies found useful were remaining active and engaged at home, attending online mental wellness sessions, practicing yoga/ meditation and spending time with friends/family. Older adults highlighted a need for more emotional support through creation of social media networks and online platforms.

Conclusion

Preliminary findings from this study emphasize a need for leveraging technology to support emotional wellbeing of older adults during lockdown and COVID restrictions.
Olfactory dysfunction and chronic cognitive impairment following SARS‐CoV‐2 infection in a sample of older adults from the Andes mountains of Argentina
Authors: Zamponi Hernan P. , Juarez‐Aguaysol Leonardo , Kukoc Gabriela , Dominguez Maria Eugenia , Pini Belén , Padilla Eduardo G , Calvó Maria , Molina‐Rangeon Silvia Beatriz , Guerrero Gonzalo , Figueredo‐Aguiar Mariana , Fumagalli Emiliano , Yécora Agustín , Brugha Traolach S , Seshadri Sudha , Snyder Heather M. , de Erausquin Gabriel A. , Gonzalez‐Aleman Gabriela ,   Alzheimer's Association CNS SARS‐CoV‐2 Consortium
Published: December 2021

Background

COVID‐19 has affected more than 150 million people. The causal coronavirus, SARS‐CoV‐2 has infected twice as many individuals who have remained asymptomatic. COVID‐19 includes central nervous system (CNS) manifestations and may result in chronic neuropsychiatric sequelae. Risk factors for COVID‐19 sequelae overlap with those for Alzheimer’s disease (AD), particularly older age and ApoE4 status. The Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) established harmonized definitions, ascertainment and assessment methodologies to evaluate and longitudinally follow up cohorts of older adults with variable exposure to COVID‐19. We present preliminary data from CNS SC2 in a prospective cohort of 234 older adult Amerindians from Argentina.

Method

Participants are ≥ 60 years recruited from the health registry of the Province of Jujuy containing all SARS‐CoV‐2 testing data (regardless of clinical status and of the result of the testing). We randomly invite older adults stratified by testing status regardless of symptom severity, a minimum of 3 months after clinical recovery (maximum 6 months); refusal to participate is <45%. Assessment includes interview with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Clinical Dementia Rating scale; neurocognitive assessment; emotional reactivity scale; and neurological assessment including semiquantitative olfactory function test, motor function, coordination and gait. We present here the results of olfactory testing and cognitive assessments.

Result

We assessed 233 infected participants and 64 controls. Average duration of formal learning is 9.35 ± 2.6 years and mean age is 66.7 ± 5.13 years. Normative data for the local population were available for Word list, Corsi Blocks, Oral Trails and Five Digit Tests and were used to normalize Z‐scores and categorize the sample in 3 groups: normal cognition (NC,44.6%); memory only impairment (MOI,21%); and multiple domain impairment (MDI,34.4%). Individuals with MDI presented severe alterations in short‐term memory; semantic memory; naming; executive function and attention compared to NC or MO groups (Table 1). Severity of cognitive impairment was significantly correlated with severity of olfactory dysfunction (χ2 = 13.82; p= 0.003) but not severity of acute COVID‐19.

Conclusion

Older adults frequently suffer persistent cognitive impairment after recovery from SARS‐CoV‐2 infection; cognitive impairment is correlated with persistent anosmia.
IL‐1 beta and TNF‐alpha play an essential role in modulating the risk of both periodontitis and Alzheimer’s disease
Authors: Wang Rachel Pei‐Hsuan , Leung Wai‐Keung , Goto Tetsuya , Ho Janice Yuen‐Shan , Chang Raymond Chuen‐Chung
Published: December 2021

Background

Periodontitis, a chronic systemic inflammatory disease, is a common health problem in the elderly. With increasing recognition that inflammation plays a key role in the pathophysiology of Alzheimer's disease (AD), our research team has been studying how systemic inflammation affects the brain immune responses. Aging is a major risk factor for both periodontitis and AD. As aging causes dysregulation of immune responses, we aimed to define the roles of cytokines in the pathogenesis of periodontitis and AD.

Methods

To induce experimental periodontitis, female WT mice were injected with heat‐killed P. gingivalis into their buccal mucosa three times per week every other week for a total of 5 weeks. Another group of mice were injected with IL‐1b and TNF‐a following the same timeline as above. Sickness Behavior and cognitive functions were assessed through open field and puzzle box test. Mandibular jaws were harvested for Micro‐CT scan. Different brain regions were harvested for biochemical analysis.

Results

Mice injected with heat‐killed bacteria had worsened long‐term memory functions. It also significantly increased periodontal bone loss, which was accompanied by increased gene expression levels of IL‐1b and TNF‐a in the gums. Significant elevated levels of pro‐inflammatory cytokines in the liver as well as different brain regions were also observed. Immunostaining revealed increased levels of phospho‐tau in WT mice injected with heat‐killed bacteria, suggesting that elevated systemic cytokine levels caused by the injection of heat‐killed bacteria can lead to the appearance of AD pathology. Another group of mice injected with IL‐1b and TNF‐a displayed hyperactivity and worsened short‐term memory functions. Injections of cytokines also induced periodontal bone loss, which was accompanied by elevated levels of inflammatory cytokines in the liver as well as different brain regions.

Conclusion

Taken together, our study revealed that increased cytokine immune response in the gums led to periodontal bone loss, brain inflammation and modulated the cognitive functions of WT mice. This research demonstrated that cytokines play a crucial role in the pathogenesis of both periodontitis and AD.

Acknowledgement: The study is supported by Health and Medical Research Fund (HMRF 04151216) to RCCC. RPHW is awarded by Hong Kong PhD Fellowship.
Alterations of plasma endocannabinoid levels in MCI and dementia patients
Authors: Kaur Daman Preet , Finn David P , Bucholc Magda , Todd Stephen , Wong‐Lin KongFatt , McClean Paula L
Published: December 2021

Background

There is growing evidence that alterations in the endocannabinoid system (ECS) co‐occur with dementia pathophysiology. Currently, limited literature is available on components of the peripheral ECS as diagnostic markers for dementia.

Methods

In the present study we analysed the concentrations of the endocannabinoids (eCBs) anandamide (AEA) and 2‐Arachidonoylglycerol (2‐AG), and their lipid congeners N‐palmitoylethanolamide (PEA) and N‐oleoylethanolamide (OEA) in plasma and serum using LC‐MS/MS. Samples were collected from healthy controls, participants with mild cognitive impairment (MCI), Alzheimer’s disease (AD) and other dementia subtypes (OD).

Results

Statistical analysis revealed significantly lower concentrations of plasma AEA (p: 0.0017), PEA (p: 0.0056) and OEA (p: 0.0015) in MCI vs. OD groups, and lower OEA levels in MCI vs. healthy controls (p: 0.0099). Plasma PEA levels in AD patients were lower compared to healthy controls (p: 0.0409) and OD groups (p: 0.0307). Additionally, plasma 2‐AG levels correlated positively with age and body mass index (p<0.0001), and negatively with ACE‐III scores (p<0.0011).

Conclusions

These results suggest that peripheral levels of eCBs vary with age and cognitive decline, and may be beneficial in differential diagnosis of dementia. Further, plasma eCB levels may be indicative of early stages of cognitive impairment like MCI, which currently is difficult to diagnose.
The role of lycopene on the hippocampus of rat model of lipopolysaccharide‐induced Alzheimer's disease
Authors: Temitope Saula Rofiat
Published: December 2021

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the sixth leading cause of dementia worldwide. According to AD hypothesis, the progression of AD begins following the accumulation of these proteins, leading to eventual synapse loss and neuronal cell death. Over the last few decades, significant advances have been made in our understanding of AD by investigating the mechanisms of the two proteins: amyloid beta and tau pathology. There are yet unanswered questions regarding the aetiology and progression of the disease.This study was designed to investigate the role of lycopene on hippocampus in lipopolysaccharide‐ induced Alzheimer’s disease.

Methods

Fifty (50) adult Wistar rats were divided into five (5) groups. Group A (The control group were given equal volume of water), Group B Lipopolysaccharides (LPS) only; given 150mg/kg body weight), Group C (curative group, given 150mg/kg of LPS followed by 15mg/kg body weight of lycopene (LYC), Group D (preventive, given 15mg/kg of LYC followed by 150mg/kg body weight of LPS), Group E (LYC only). The rats were subjected to neurobehavioral protocols. After sacrifice, the brain sections were processed and stained for H&E, Silver, LUXOL‐FAST BLUE, and Masson Trichrome stains.

Results

The results revealed that LPS induced significant reduction in body and brain weights, reference memory and neuronal parameters. There was significant histologically lesions, demyelination and increased neuroinflammation.

Conclusions

the study demonstrated that Lycopene exhibited neuroprotective effects by mitigating oxidative stress, suppressing production of inflammatory cytokines, and attenuating the pathologic lesions associated with LPS AD modelin the hippocampus.
mRNA‐Binding Protein DJ‐1 as a pivotal protein in AD pathology
Authors: Uneri Ayse , Niere Farr , Macauley Shannon L , Ma Tao , Keene C. Dirk , Craft Suzanne , Raab‐Graham Kimberly F
Published: December 2021

Background

Alzheimer’s Disease (AD) is a complex neurodegenerative disorder of the synapse, characterized by the accumulation of amyloid beta plaques and neurofibrillary tangles. We have recently shown that Parkinson Protein 7, DJ‐1, is upregulated by mTORC1 activity, and is a translational hub that is predicted to coordinate the expression of a population of synaptic proteins (Niere et al., 2016). This cellular function of DJ‐1 is mediated through its RNA‐binding properties, yet many of its target mRNAs are unidentified, and the effects of this protein‐mRNA association are not well‐defined.

Method

Synaptically increased DJ‐1 expression was determined by Western blotting of synaptoneurosomes from AD patients (Niere et al., 2020), and APP/PS1 and P301S mouse models of AD. DJ‐1 target mRNAs were first bioinformatically identified using a modified consensus sequence of DJ‐1 protein (van der Brug et al., 2008), and confirmed via RNA‐immunoprecipitation of DJ‐1 from WT mouse cortices. FMR1KO mouse cortices were used as a negative control.

Result

Synaptic DJ‐1 expression is increased in a preclinical mouse model of AD exhibiting plaque pathology, and AD patients. Interestingly, there is no change in synaptic DJ‐1 levels in the P301S mouse model, which presents neurofibrillary tangles. We bioinformatically identified that mRNA coding for the RNA‐binding protein FMRP, and tau‐tubulin kinase 1 (TTBK1), known for phosphorylating pathogenic tau, as potential targets for DJ‐1, and confirmed it via RNA‐immunoprecipitation. Furthermore, the protein levels of FMRP is significantly decreased in the synapses of AD patients and APP/PS1 mice, while there is no change in the P301S model consistent with no change in DJ‐1 expression.

Conclusion

Decrease in FMRP in AD synapses where DJ‐1 expression is high suggests that DJ‐1 is a translational repressor of FMRP. FMRP binds to the mRNA of amyloid precursor protein (APP), the building block of amyloid beta plaques. Therefore, DJ‐1’s capacity to bind both Fmr1, coding for a protein which is known as a translational suppressor of APP mRNA (Borreca et al., 2016), and Ttbk1, a tau kinase involved in tau phosphorylation and aggregation (Sato et al., 2006) suggests that DJ‐1 might be at the crossroads of both AD hallmark pathologies.
Focus Ultrasound‐Induced Blood‐Brain Barrier opening enhances anti‐pGlu3 Aβ mAb delivery and amyloid‐beta plaque clearance
Authors: Bathini Praveen , Sun Tao , Shi Qiaoqiao , Zhang Yongzhi , Taudte Nadine , Schenk Mathias , Hettmann Thore , Schilling Stephan , McDannold Nathan , Lemere Cynthia A
Published: December 2021

Background

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood‐brain‐barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance delivery of therapeutic agents to CNS. Our lab has shown that an mAb (07/2a), targeting N‐terminally truncated and modified toxic Aβ species, reduced pGlu3 Aβ and general Aβ cerebral plaques in aged APP/PS1dE9 mice. Here, we asked whether FUS‐induced BBB opening enhances the delivery of 07/2a mAb and whether it has any additive effect on cognition or plaque clearance.

Methods

First, 24 mo‐old APP/PS1dE9 mice were i.v. infused with a single dose of 300 µg 07/2a with or without hippocampal FUS sonication (n=5/group) with i.v. infused Optison microbubbles and euthanized 4 or 72 h later; brain levels of antibodies were measured by ELISA. Next, 16 mo‐old APP/PS1dE9 mice were treated weekly for 3 weeks with PBS (n=9), 500 µg 07/2a alone (n=9), FUS alone (n=7) or 07/2a + FUS combination (n=6). Behavioral testing in the Water T Maze (WTM) was performed 1‐2 weeks later followed by euthanasia.

Results

FUS treatment increased 07/2a mAb levels in brain by 5.9‐fold 4 hr (41.7 pg/mg for mAb alone, vs. 244 pg/mg mAb+FUS; t=3.48, p<0.005) and 5.5‐fold (mean=31.5 pg/mg for mAb alone, vs. 173 pg/mg for mAb+FUS; t=2.9, p<0.05) 72 hr post‐treatment. Immunohistochemistry confirmed a significant increase in IgG2a mAb staining in the mAb+FUS treated mice at 4 hr (p=0.007) and a strong trend in the mAb+FUS treated mice at 72 hr after treatment compared to mAb alone. Three weekly treatments of 07/2a improved cognition however, when combined with FUS, this improvement occurred faster and in a higher percentage of mice and led to reduced hippocampal plaque load compared to PBS control mice.

Conclusions

Transient opening of the BBB by FUS increased 07/2a delivery to the brain, improved cognition, and enhanced Ab clearance in aged APP/PS1dE9 mice, suggesting that FUS increased efficacy of the 07/2a mAb.
Defining the role of PLD3 in Alzheimer’s disease pathology
Authors: Rosene Matthew J , Hsu Simon , Martinez Rita , Norton Joanne , Yan Ping , Cirrito John R , Lee Jin‐Moo , Cuervo Ana Maria , Goate Alison M. , Cruchaga Carlos , Karch Celeste M.
Published: December 2021

Background

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid‐β (Aβ) in the brain. We recently identified coding variants in the phospholipase D3 (PLD3) gene that double the risk for late onset AD.

Method

We examined the impact of PLD3 risk variants on PLD3 and Aβ metabolism using CRISPR/Cas9 in induced pluripotent stem cells (iPSC). We then modeled the PLD3 expression patterns observed in AD brains in immortalized cell and AD mouse models. Lysosomal function was assessed in human brain tissue.

Result

PLD3 A442A disrupts a splicing enhancer binding site and reduces PLD3 splicing in human brains. Differentiation of PLD3 A442A and isogenic control iPSCs into cortical neurons produced cells that were morphologically similar. At the molecular level, PLD3 A442A neurons displayed a similar defect in PLD3 splicing as was observed in human brains and a significant increase in Aβ42/Aβ40 compared with isogenic control lines. Thus, PLD3 A442A is sufficient to alter PLD3 splicing and Aβ metabolism. PLD3 expression was significantly lower in AD brains compared with controls, and PLD3 expression was highly correlated with expression of lysosomal genes. Thus, we sought to determine whether PLD3 contributes to Aβ accumulation in AD via disrupted Aβ metabolism. We found that overexpression of PLD3 in immortalized cells decreased Aβ levels while shRNA silencing of Pld3 increased Aβ levels. In an AD mouse model, overexpression of PLD3 in hippocampal neurons produced decreased interstitial fluid (ISF) Aβ levels and accelerated Aβ turnover. Conversely, knocking out Pld3 increased ISF Aβ, reduced Aβ turnover, and increased APP protein levels. Knocking out Pld3 overtime lead to altered amyloid morphology. To begin to determine whether PLD3 influences Aβ turnover via the lysosome, we isolated lysosomal fractions from human AD and control brains. PLD3 was enriched in lysosomal subfractions and PLD3 distribution in these subfractions was altered in AD. Furthermore, PLD3 stability in the lysosomal fractions was disrupted in AD brains.

Conclusion

Together, our findings demonstrate that PLD3 promotes Aβ clearance through pathways involving lysosomal degradation.