bluuebunny/crossref_metadata_2025 huggingface dataset:
Leukotriene receptor antagonist use is associated with slower cognitive decline in Alzheimer’s disease
Authors: Xiong Lisa Y. , Ouk Michael , Wu Che‐Yuan , Rabin Jennifer S. , Lanctôt Krista L. , Herrmann Nathan , Black Sandra E. , Edwards Jodi D. , Swardfager Walter
Published: December 2021

Background

Repurposing of leukotriene receptor antagonists (LTRAs), originally developed for asthma, is currently being explored in the treatment Alzheimer’s disease (AD). Animal studies have shown that administration of the LTRA montelukast has neuroprotective effects and can improve memory and cognition in rodents; however, there is limited evidence supporting the neuroprotective effects of LTRAs in humans.

Methods

Participants with AD dementia were identified in the National Alzheimer's Coordinating Center database. LTRA (montelukast or zafirlukast) users were propensity matched 1:3 to non‐users on age, sex, education, body mass index, smoking history, concomitant use of medications for dementia and other respiratory medications (for allergy, chronic obstructive pulmonary disease, and asthma), APOE ε4 carrier status, CDR® Dementia Staging Instrument global score, and vascular brain disease. Cognitive domains including immediate and delayed memory (Weschler Memory Scale Revised – Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol), and language (Animals, Vegetables, and Boston Naming Test) were compared between users and non‐users in mixed‐effects linear or Poisson regression models, as appropriate for the data distribution, yielding unstandardized regression coefficients (B) and rate ratios (RR), respectively.

Results

Among n=604 people with AD dementia (mean age 75.3±10.0 years, 59.3% female, mean education 14.0±4.0 years, 55.1% APOE ε4 carriers, mean follow‐up 2.5±2.6 years), LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol test (Β=1.466 [0.253,2.687] symbols/year), and a slower decline in language, as measured by Animals (Β=0.541 [0.215,0.866]animals/year), Vegetables (B=0.309 [0.056,0.561] vegetables/year), and the Boston Naming Test (B=0.529 [0.005,1.053] words/year). Effect sizes were relatively small (range 0.069‐0.101) and persisted after controlling for a 10% false discovery rate. LTRA use was not associated with a change in performance for immediate (RR=1.047 [0.970,1.129]) or delayed memory (RR=1.062 [0.929,1.215]).

Conclusion

These results indicate that use of an LTRA may have benefits for preserving function for select cognitive domains in individuals with AD dementia. The leukotriene pathway may represent a target for the treatment of AD dementia and the role of leukotrienes and their receptors in cognitive decline warrants further investigation.
A machine learning approach to predict reversion from mild cognitive impairment to normal cognition: A population‐based cohort study
Authors: Sha Feng , Bi Jiefeng , Wei Chang , Zhao Ziyi , Li Bingyu
Published: December 2021

Background

Predicting the probability of the reversion from mild cognitive impairment (MCI) to cognitively normal (CN) status can inform preventive treatments at individual, institutional and social level. This study aims to build a prediction model using a machine learning approach for reversion from MCI to CN status.

Method

The study included 7,422 participants above 65 years old with MCI from Chinese Longitudinal Health Longevity Survey (Figure 1). LightGBM was used to build a prediction model of 154 variables, including individual and household socioeconomic status, dietary/lifestyle, cardiometabolic, psychological factors and history of diseases. SHAP values were used to interpret the impact of the top 40 variables that contributed to the LightGBM model. Multivariable Cox regression with elastic net penalty was also conducted for comparison. Model performance was assessed according to a range of learning metrics including area under the receiver operating characteristic curve (AUC).

Results

1,604 (21.6%) participants reversed from MCI to CN with a median follow‐up of 2.8 years. The top 40 features were presented in the figure 2. The concordance index of the LightGBM model was 0.71, which is much higher than the traditional multivariable Cox regression with elastic net penalty (0.66).

Conclusion

The machine learning approach could develop a more accurate early identification of recovery of MCI patients. The predicting can guide the recovery process of MCI patients.
Comprehensive geriatric assessments for long‐term and home care settings and digital platforms available to support their applicability: A systematic review
Authors: Ulate Mauricio Molinari , Asl Aysan Mahmoudi , Vidales Esther Parra , Sánchez Juan Luis Muñoz , Martin Manuel Angel Franco , van der Roest Henriëtte G.
Published: December 2021

Background

Integrated care delivery is regarded as the most effective way of care provisioning to tackle challenges of dementia care, such as uncoordinated care, risk of hospitalizations, care planning and unmet needs. As Comprehensive Geriatric Assessments (CGAs) incorporate the key principles of integrated care, implementing CGAs in care practice might be highly relevant. However, this implementation should be supported by Digital Health Interventions in order to reach the full CGA capacity.

Aims

: To present the state‐of‐the‐art evidence on available CGAs for long‐term and home care, and digital platforms supporting the administration of CGAs.

Methods

Two search strategies were conducted in PubMed, CINAHL, and Web of Science. One focused on the validity and reliability of available CGAs for long‐term and home care settings, and the second search comprised digital platforms that support CGAs. Studies in English and Spanish and published up to July 30, 2020 were considered.

Results

A total of 73 studies reporting on the validity/reliability of 14 different CGAs, and five papers describing four digital platforms supporting CGAs were identified. Most of the CGAs covered a wide range of domains, evidence for good to excellent validity and reliability was reported for various instruments. Digital platforms showed some limitations and barriers regarding their usability and feasibility.

Conclusion

Foremost, strong evidence of good to excellent validity and reliability was found for the Resident Assessment Instrument‐Minimum Data Set (RAI‐MDS) and subsequent updated instruments, similar results have been reported for multiple countries. For this reason, we recommend the use of its latest versions for long‐term care facilities and home care, the interRAI LTCF and interRAI HC. Regarding the digital platforms supporting CGAs, the inclusion of safe data storage, automatic notifications for assessment completion, individualized profile reports, automatic calculation of final outcomes, and facilitation of multidisciplinary assessments, were identified as key features to enhance their implementation. This project is part of the Marie Skłodowska Curie Actions Innovative Training Network H2020‐MSCA‐ITN, under grant agreement number 813196.
Recommendations of the International Working Group for the clinical diagnosis of Alzheimer’s disease
Authors: Dubois Bruno , Villain Nicolas , Frisoni Giovanni , Rabinovici Gil D. , Sabbagh Marwan Noel , Cappa Stefano , Bejanin Alexandre , Bombois Stéphanie , Epelbaum Stéphane , Teichmann Marc , Habert Marie‐Odile , Nordberg Agneta K. , Blennow Kaj , Galasko Doug R. , Stern Yaakov , Rowe Christopher C. , Salloway Stephen P. , Schneider Lon S. , Cummings Jeffrey L. , Feldman Howard
Published: December 2021

Background

In 2018, the National Institute of Aging and the Alzheimer Association proposed a purely biological definition of Alzheimer’s disease (AD) relying on biomarkers. While the intended use of the framework was for research purposes, it has engendered debate and challenges regarding its application in everyday clinical practice.

Method

We performed a literature review and pointed out the limitations of the current purely biological definition of AD.

Result

Neuropathological studies have shown that amyloid β plaques and tau tangles are often accompanied by other pathologies, so ascribing the clinical phenotype to an amyloid or tau biomarker result might be difficult. In asymptomatic people, the detection of abnormal biomarkers is fraught with problems relating to uncertainty about the prognosis, and complex judgments and ethical issues about communicating results. Even defining biomarker categories is not simple, because methods for determining positivity are not always straightforward and nominally negative biomarker values can be associated with future cognitive decline. New clinical framework proposition: To address these concerns, the IWG advocates a return to Alzheimer’s disease as a clinical‐biological entity, characterised by amyloid β and tau biomarkers plus a typical clinical phenotype. We advise against measurement of amyloid β and tau biomarkers in asymptomatic people because of unreliable predictive power; nevertheless, we do provide a risk stratification scheme for such people, and abnormal amyloid β and tau biomarkers are thought to confer high risk. However, such individuals are categorised as being asymptomatic at risk of progression, not as having AD. In symptomatic people, we stress the importance of a careful clinical evaluation in view of the common occurrence of multiple pathologies, borderline biomarker measurements, and conflicting findings.

Conclusion

These new recommandations of the IWG are the opportunity to debate about the definition of AD and the use of biomarkers in clinical practice and pharmacological trials. This developing topic should open a significant discussion between AD specialists (both physicians and scientists) at the 2021 AAIC.
Shining new light on dementia treatment: ADAS‐Cog and quantitative EEG evidence of cognitive improvement in early and mid‐stage dementia using self‐administered 1070 nm transcranial near‐infrared photobiomodulation
Authors: Berman Marvin H
Published: December 2021

Background

The current evidence supporting nonpharmacologic treatment of dementia has focused mainly on environmental or interactive interventions, e.g., music, sensory stimulation, simulated presence, and validation therapies. Exercise and light therapy improved/maintained activities of daily living, while cognitive stimulation, exercise and reminiscence improved cognition. The strongest evidence for reducing emotional disorders so far has employed music, psychological interventions and reminiscence. PubMed lists 918 citations related to non‐pharmacological treatments for dementia with music therapy and behavioral management techniques being the most efficacious showing modest improvements at best. Non‐pharmacologic treatment interventions directed at reversing both cognitive and behavioral symptom of dementia are small, few in number and with wide variation in defining outcome measures, and little comparative data across approaches to guide further research efforts or systematic clinical applicability. Photobiomodulation using brief, daily, pulsed LED‐driven transcranial infrared light stimulation, has been shown to markedly alter both cognitive and behavioral symptoms in people with mild to moderate dementia. Improved functioning has been documented by both standard neuropsychological testing and noninvasive Quantitative electroencephalographic (QEEG) measures of functional connectivity. This presentation describes a multi‐site, randomized, placebo controlled, at‐home, self‐administered treatment protocol employing pulsed transcranial and intraocular 1068nm near‐infrared light to achieve reversal of cognitive decline, and improve dementia patient’s physical and interpersonal behavior. Study subjects (n=100) were evaluated at two locations at baseline, midpoint (30 days) and termination (60 days) using both Quantitative EEG and ADAS‐Cog and caregiver evaluation of subject’s change in ADLs. This trial was a replication of an earlier pilot trial and a recent safety/feasibility trial with no adverse events reported in any study. MMSE improved 21.0%, 4.8 points in the active treatment group and 1.6 points in the placebo group. Sleep duration increased in the active treatment group by an hour after 8 days of treatment and caregivers noted improved mood, energy, and positive engagement in daily activities. None of these functional changes were noted in the placebo arm subjects. Active group’s clock drawing improved 20% and no change in the control group. Logical memory recall improved 3.3 points (p< .03) and time to completion of Trails A&B decreased 23.7% (p<.03).
Safety and efficacy of Lomecel‐B in patients with mild Alzheimer’s disease: Results of a double‐blinded, randomized, placebo‐controlled phase 1 clinical trial
Authors: Oliva Anthony A. , Brody Mark , Agronin Marc , Herskowitz Brad , Bookheimer Susan Y , Hitchinson Ben , Ramdas Kevin , Wishard Tyler , McClain‐Moss Lisa , Diaz Liliana A. , Yousefi Keyvan , Perez Carmen , Fuquay Ana , Rodriguez Savannah , Hare Joshua M. , Baumel Bernard
Published: December 2021

Background

Lomecel‐B is a formulation of allogeneic medicinal signaling cells (MSCs), which exert pleiotropic mechanisms of action (MOAs) with potential to simultaneously target multiple pathophysiological features of Alzheimer’s disease (AD).

Method

We conducted a double‐blinded, randomized, placebo‐controlled trial (ClinicalTrials.gov: NCT02600130). Mild AD patients (Table) were infused with Lomecel‐B at 20 (20M, N=15) or 100 million cells (100M, N=10), or placebo (N=8). Eligibility screening included clinical evaluation, MRI to exclude other etiologies, and beta‐amyloid tracer PET to confirm AD. Scheduled follow‐ups were conducted through 1‐year post‐treatment. The primary endpoint was safety. Pre‐specified secondary endpoints evaluated efficacy in neurocognitive/neuropsychological, quality‐of‐life (QOL)/activities of daily living (ADL), and biomarker domains.

Result

Lomecel‐B was well‐tolerated and did not trigger safety stopping rules, meeting the primary endpoint. Efficacy endpoints were improved in the Lomecel‐B groups. Whereas the Mini Mental State Exam (MMSE) declined in placebo by 2.99±1.12 points at Week 13 (p=0.0337; 95%CI ‐5.84 – ‐0.31), the 20M Lomecel‐B group showed minimal decline (difference from placebo: 2.69±1.39 points; p=0.0182; 95%CI 0.51 – 4.97). This difference persisted over one year (Figure). On the QOL‐AD patient version, the 20M Lomecel‐B group significantly improved versus placebo at Week 26 by 3.85±1.94 points (p=0.0444; 95%CI 0.13 – 9.12). On the ADCS‐ADL, the placebo group significantly declined at Week 26 by 9.27±2.78 points (p=0.0211; 95%CI ‐17.83 – ‐2.10), and was significantly worse versus 20M Lomecel‐B by 6.95±3.46 points (p=0.0118; 95%CI 1.99 – 13.94). In contrast, these assessments did not significantly differ in the 100M Lomecel‐B group versus placebo. Anti‐inflammatory (IL‐10, IL‐12, sIL‐2Rα) and pro‐vascular (VEGF, IL‐4, IL‐6) serum biomarkers were significantly higher in both Lomecel‐B groups versus placebo, with 100M Lomecel‐B generally showing the greatest rises. Left hippocampal volume increased in the 100M Lomecel‐B group versus placebo at Week 13 (p=0.0311).

Conclusion

These results support the safety and clinical potential of Lomecel‐B for AD. These hypothesis‐generating results also revealed potentially important biomarkers which are consistent with multiple MOAs of Lomecel‐B. Ongoing investigation of Lomecel‐B for AD in larger clinical trials powered for clinical efficacy is warranted. This study was supported through Alzheimer’s Association Part the Cloud Challenge on Neuroinflammation grants #PTC C‐16‐422443 and PTC‐CS‐19‐623225.
Design of a patient‐ and investigator‐blind, randomized, placebo‐controlled study to evaluate efficacy, safety, and tolerability of bepranemab, UCB0107, in prodromal to mild Alzheimer’s disease: The TOGETHER Study, AH0003
Authors: Barton Matthew E , Byrnes William , Mesa Irene Rebollo , Bloemers Jos , Maguire Ralph Paul , Bouw Rene , Tesseur Ina , Ewen Colin , Scheltens Philip
Published: December 2021

Background

Bepranemab is a recombinant, humanized, full‐length immunoglobulin G4 monoclonal antibody that binds to a central tau epitope (amino acids 235–250). Bepranemab is being developed to block or reduce the spread of tau pathology in people living with tau‐mediated diseases, like Alzheimer’s disease (AD).

Method

TOGETHER (AH0003; NCT04867616) is a global, multicenter, patient‐blind, investigator‐blind, placebo‐controlled, parallel‐group study, investigating the efficacy, safety, and tolerability of bepranemab (intravenously, every 4 weeks) versus placebo in patients with prodromal (40%) or mild (60%) AD over an 80‐week treatment period, followed by an optional 48‐week open‐label extension (OLE). The primary objective is the change from baseline to Week 80 in the Clinical Dementia Rating (CDR) Scale Sum of Boxes total score. Secondary objectives include: pharmacokinetics (PK); safety and tolerability; the effect of bepranemab on tau positron emission tomography (PET) imaging at Weeks 56 and 80; and the changes from baseline in the 14‐item Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog14), Amsterdam‐Instrumental Activities of Daily Living, and Mini‐Mental State Examination (MMSE) at Weeks 56 and 80. The OLE will assess the long‐term safety and tolerability of bepranemab. Approximately 150 patients per arm will be enrolled across 3 study arms (low‐dose and high‐dose bepranemab, and placebo; randomized 1:1:1). Eligible patients will meet the National Institute of Aging‐Alzheimer’s Association (NIA‐AA) 2018 Stage 3 or 4 definitions of prodromal or mild AD, respectively. Patients will have a global CDR score indicative of prodromal AD (0.5) or mild AD (0.5 or 1.0) and a CDR‐Memory Box score ≥0.5 at screening and baseline. Patients will have a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status, MMSE ≥20 at screening and must meet the NIA‐AA 2018 definition of cerebral beta‐amyloid (Aβ) accumulation, by either a positive centrally read PET scan or a positive cerebrospinal fluid pTau181/Aβ1‐42 ratio.

Result

Patient enrollment and assessment will begin in Quarter 2 2021.

Conclusion

TOGETHER is a proof‐of‐concept study that will employ clinical outcome measures, imaging, PK, biomarkers, and safety to assess the ability of bepranemab to slow the progression of AD when administered in the prodromal/mild stages of disease.
A simple Mini‐Mental State Exam subscale formula to help differentiate Alzheimer's disease from dementia with Lewy bodies
Authors: Bakir Danah , Goel Srishti , Ala Tom
Published: December 2021

Background

Although there are clinical criteria for the diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), the two conditions may sometimes be difficult to differentiate. Prior research has documented that the two conditions often have striking neuropsychological differences, and there have been a number of reports promoting the ability of simple screening tests to help the diagnostic accuracy of the clinician. These screening tests, however, have been limited in their specificity. Building upon previous research from our group and others, we now report a simple manipulation of the Mini‐Mental State Exam (MMSE) subscale scores that greatly improves the specificity of the screening test.

Method

We studied all AD and DLB patients who visited our dementia clinic during an 18‐month period, including both new and follow‐up visit patients. All who had an MMSE administered to them were included. All MMSE scores were included. The first MMSE recorded for each patient was studied.

Result

We studied the MMSEs from 136 AD and 24 DLB patients. The mean patient age was 77.8 ± 11.1 for AD, 78.3 ± 8.7 for DLB. Mean MMSE score was 20.0 ± 6.0 for AD, 21.8 ± 5.1 for DLB; MMSE range 1‐30 for AD, 10‐28 for DLB. Many different formulae were studied using the MMSE subscales of Memory (3 points max), Attention (5 points max), and Pentagon‐copying (1 point max) to determine which was the best to differentiate AD from DLB. The simple formula of the Pentagon score minus the Memory score (P‐M, range 1 to ‐3) provided the best discrimination between the AD and DLB patient groups. For P‐M scores = 1, the specificity of the equation to identify AD was 0.92. For P‐M scores < 0, the specificity to identify DLB was 0.85. The sensitivities for the P‐M equation were 0.43 for AD (scores = 1) and 0.46 for DLB (scores < 0).

Conclusion

The simple MMSE subscale formula of Pentagon score minus Memory score (P‐M) provided good specificities to identify AD patients (0.92) and LBD patients (0.85) within our cohort of AD and DLB patients. A weakness of the P‐M equation was relatively weak sensitivity.
Machine learning on combined neuroimaging and plasma biomarkers for triaging participants of secondary prevention trials in Alzheimer’s disease
Authors: Cumplido‐Mayoral Irene , Salvadó Gemma , Shekari Mahnaz , Operto Grégory , Falcon Carles , Milà‐Alomà Marta , Niñerola‐Baizán Aida , Molinuevo Jose , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Vilaplana Verónica , Gispert Juan Domingo
Published: December 2021

Background

Plasma biomarkers have demonstrated excellent agreement with established markers of amyloid‐β (Aβ) positivity (PET and CSF) to identify patients with symptomatic AD. However, their predictive capacity in cognitively unimpaired (CU) individuals is lower. In this work, we aimed at assessing whether structural MRI features could improve the capacity of machine learning algorithms applied to plasma biomarkers to identify Aβ positive CU individuals.

Method

We included 344 CU individuals from the ALFA+ study, with available T1w MRI, Aβ PET and plasma measurements for p‐tau181, p‐tau231, and GFAP. We determined the capacity to predict Aβ+ according to PET visual read of plasma biomarkers in combination with clinical data (age, sex, education, MMSE, and APOE genotype) and MRI‐derived measurements. We trained Random Forest classifiers with clinical, clinical and plasma, clinical and MRI; and clinical, plasma and MRI data. The MRI‐selected measurements consisted of Jack’s AD‐signature and the two features best predictive of Aβ+: left‐lat‐inf‐ventricle and left caudal‐anterior‐cingulate as determined with Freesurfer 6.0. We conducted ROC and Precision‐Recall analyses and calculated savings as the percentage difference of costs between standard trial recruitment and a triaging step with the different classifiers. The threshold for positivity prediction was chosen to maximize savings and the precision‐recall ratio. We computed ROC‐AUC, PPV, sensitivity and savings as metrics for the comparison.

Results

The mean centiloid values of Aβ+ subjects (13.66%) and Aβ‐ were 33.73 and ‐1.82, respectively (Table 1). ROC‐AUCs for the classifiers to detect Aβ+ was 0.723 for clinical information; 0.861 for clinical and plasma measurements; 0.711 for clinical and MRI; and 0.871 for clinical, plasma and MRI. Savings associated with the best classifier (clinical + plasma + MRI) would translate in savings (95%CI) of 52.8% (49.0, 56.3) in recruitment costs. See Figure 1 for all the metrics’ results.

Conclusion

Machine learning algorithms on plasma biomarkers achieved a high accuracy on predicting a positive visual read on amyloid PET scans in cognitively unimpaired individuals. MRI biomarkers marginally improved the predictive capacity. Used as a triaging method, such an algorithm would result in a reduction of over 50% in the cost to identify participants for secondary prevention trials.
Drivers and barriers to participation of Black and Hispanic groups in Alzheimer's disease clinical trials: A qualitative study
Authors: Montenigro Philip H , Tse Bob , Wilson Kate , Butts Cherie
Published: December 2021

Background

For years, studies have reported that Black and Hispanic groups distrust physicians and are less likely to enroll in clinical trials (CT). For example, despite having nearly twice the risk for Alzheimer’s disease (AD) vs Whites, Black and Hispanic groups represent less than 5% of participants in AD CTs. The purpose of this study was to engage major stakeholders across the healthcare ecosystem in the United States to assess drivers and barriers to Black and Hispanic group participation in AD CTs.

Methods

In this study, we performed interviews of major stakeholders, including patients, care partners, physicians, investigators, trial‐coordinators, and payers. Semi‐structured questionnaires were developed to identify rational, emotional, and subconscious drivers and barriers to Black and Hispanic group participation in CTs. We surveyed individuals of different geographies, genders, ages (20‐65), locations (rural‐urban), education (some high school‐graduate school), and employment (unemployed‐full‐time). Responses from physicians and patients both with and without CT experience were also collected.

Results

We found a major barrier to CT participation reported by Black and Hispanic persons was mistrust. Additionally, patients reported confusion about their AD diagnosis and feared psychiatric side‐effects of study treatments. Additional barriers included misconceptions about trials and limited awareness of the potential benefits (e.g., slowing disease progression) of treatments. While there is limited research on drivers for CT participation, respondents in this study were motivated by the potential benefit to their communities. Among physicians, barriers to participation included lack of familiarity with AD screening methods and lack of awareness of CTs in general. Another barrier among physicians was a belief that Black and Hispanic patients would not understand a diagnosis of AD, instead opting to use less specific language such as “memory decline” with these patients.

Conclusion

Inclusion of Black and Hispanic participants in AD CTs is necessary to determine the safety and efficacy of potential treatments for AD in these groups. This research identified a critical area of focus for health equity efforts: intentional engagement with physicians for optimal education, access, and inclusion in AD CTs.
Cortical neuroanatomical changes related to specific neuropsychological deficits in subcortical vascular cognitive impairment
Authors: Kang Sung Hoon , Park Yu Hyun , Chin Juhee , Seo Sang Won
Published: December 2021

Background

Neuropsychological test‐specific neural substrates in subcortical vascular cognitive impairment (SVCI) are expected to differ from those in Alzheimer’s disease‐related cognitive impairment (ADCI) but the details are unclear. To determine neural substrates related to cerebral small vessel disease, we investigated the correlations between cognitive dysfunctions measured by standardized neuropsychological tests and cortical thickness in a large sample of participants with amyloid negative (Aβ (‐)) SVCI.

Method

One hundred ninety‐eight participants with Aβ (‐) SVCI were recruited from the memory clinic between November 2007 to August 2018. To acquire neural substrates, we performed linear regression using the scores of each neuropsychological test as a predictor, cortical thickness as an outcome, and age, sex, education years, intracranial volume and white matter hyperintensity (WMH) as confounders.

Result

Poor performances in each neuropsychological test were associated with cortical atrophy in certain brain regions regardless of WMH. Especially, not the medial temporal but the frontal and posterior cingulate regions with cortical atrophy were mainly associated with memory impairment. Poor performance in animal fluency was more likely to be associated with cortical atrophy in the left hemisphere, while poor performance in the visuospatial memory test was more likely to be associated with cortical atrophy in the right hemisphere.

Conclusion

Our findings suggested that cortical atrophy was an important factor of cognitive impairment in Aβ (‐) SVCI regardless of WMH. Furthermore, our findings might give clinicians a better understanding of specific neural substrates of neuropsychological deficits in patients with SVCI.
Differences in temporal AD biomarker trajectories according to sex and APOE genotype: Implication of importance of striatal amyloid
Authors: Chun Min Young , Kim Jun Pyo , Kim Soo‐Jong , Jang Hyemin , Kim Hee Jin , Na Duk L. , Seo Sang Won
Published: December 2021

Background

Accumulation of β‐amyloid (Aβ) plaques and neurofibrillary tangles are core components of Alzheimer's disease (AD) pathogenesis. Longitudinal in vivo observations of AD pathologic changes using amyloid and tau positron emission tomography (PET) enable us to obtain AD biomarkers' hypothetical trajectory curves. However, the difference in disease progression by striatal Aβ deposition, sex, and apolipoprotein E (APOE) genotype has not been explained with trajectory curves. The aim of this study is to develop the trajectory in accumulation of cortical and striatal Aβ and tau deposits. We also tried to investigate the differences in sex and APOE genotype on trajectory curves.

Method

We obtained 817 subjects from the Alzheimer’s Disease Neuroimaging Initiative database, who showed either 18F‐florbetapir (AV45) PET positivity at least once or AV45 PET negativity with normal cognition. We Z‐transformed each value based on Aβ‐negative, cognitively normal subjects. Instead of obtaining a single rate value (∆Z/∆t) per subject, we calculated the slope for every interval of PET scans. For each biomarker, we fitted a penalized spline to model the slope of Z value as a nonlinear function of baseline Z value. Using the fitted splines, we obtained the predicted Z curves as a function of time and developed trajectory curves.

Result

Among the subjects, 534 subjects were available for AV45 PET analysis and 163 subjects underwent 18F‐flortaucipir PET. While cortical Aβ accumulation rate increased until Z value reached 4.33 and decreased subsequently, ∆Z/∆t for the striatal Aβ and tau stayed more constant. Time from Z=0 to Z=2 was the longest for tau PET (22.6 years) and shortest for cortical Aβ (14.9 years). For cortical Aβ, Z values of males reached 1.7 years earlier than females. However, for striatal Aβ, males took 2.8 more years than females to reach Z=2. Also, APOE ɛ4 carriers showed faster progression for all biomarkers.

Conclusion

This study shows that Aβ accumulates in the striatum after cortex and then tau protein, which is consistent with the amyloid cascade hypothesis. The trajectory curves differ according to sex and APOE genotype. Therefore, prognosis and treatment should be approached differently in clinical practice with respect to striatal involvement, sex, and APOE genotype.
Impact of Covid‐19 pandemic on lifestyle in a middle‐aged and elderly population
Authors: Wong Zi Xuen , Phua April , Chew Kimberly Ann , Mohamed Jameelah Sheik , Pérez Kristal Morales , Mangialasche Francesca , Kivipelto Miia , Chen Christopher
Published: December 2021

Background

Mandated lockdowns and restricted activity in response to the COVID‐19 pandemic has affected our everyday life1. Seniors, in particular, have been affected due to higher morbidity and mortality2. The World‐Wide‐FINGERS‐SARS‐CoV‐2 survey is part of an international project, consisting of members of the World‐Wide FINGERS (WW‐FINGERS) Network for dementia risk reduction and prevention3. The study aims to measure the direct and indirect effects of the outbreak in midlife and older age. Preliminary results of this ongoing study is focused on lifestyle changes.

Method

The survey commenced in September 2020.Participants aged 45 and above were recruited from existing research cohorts, memory clinic patients and community subjects. Sociodemographic factors, health related information, impact on lifestyle and behavior as well as personality factors were collected through three modalities: self‐administered online survey, telephone survey and in person with research staff.

Result

At present, 167 non‐demented participants were included in the current preliminary analysis. Majority of the participants were Chinese (83.2%), aged 65 and above (59.3%), male (58.1%), with at least secondary education (80.8%). The survey found that 61.6% of the participants reported decreased contact with friends and relatives, with 22.2% reporting an increase in loneliness. Approximately one‐third of the participants reported a decrease in physical activity (35.9%) and an increase in food intake (30.5% in snacking habits; 25.1% in fruits consumption). Approximately half of the participants reported increase in usage of internet and digital services to keep in contact with family and friends.

Conclusion

The COVID‐19 pandemic has produced measurable impacts on lifestyle‐related behavior of individuals. The decrease in social interaction and increase in loneliness during the pandemic due to government directive, along with concerns of contracting the virus highlight the importance of digital services for and digital literacy in older adults to keep them connected and supported remotely.
Healthcare services for people with dementia in Vietnam: A situational analysis
Authors: Dang Thu Ha , Tran Kham , Esterman Adrian , Roughead Elizabeth E , Brodaty Henry , Hinton Ladson , Kim Giang Bao , Kurrle Susan , Crotty Maria , Pham Thang , Le Pham Tuan , Hoang Phuong , Nguyen Tuan Anh
Published: December 2021

Background

Vietnam is facing rapid population ageing, with one in four Vietnamese citizens being over 60 years old by 2050. This has contributed to a boom of chronic and non‐communicable diseases, such as dementia. In order to develop a national dementia plan as recommended by the World Health Organization (WHO) and increase the preparedness of the healthcare system to tackle dementia, a situational analysis of the current healthcare services related to dementia is needed.

Method

In late 2019, we conducted a situational analysis desk review of the healthcare system in Vietnam, focusing on health service delivery for the elderly, using the guidance developed by the Strengthening Responses to Dementia In Developing Countries (STRiDE) project. The WHO’s six‐building‐block framework was used to analyse the healthcare system in Vietnam, followed by the thematic and SWOT (Strengths, Weaknesses, Opportunities and Threats) analyses of dementia‐related healthcare services.

Result

Although Vietnam has achieved significant improvement in healthcare in general, there are still inefficiencies in health service delivery. There are also discrepancies in health service readiness and quality across areas of healthcare. Despite of extensive primary healthcare system, grassroots‐level facilities have inadequate infrastructure required for basic care delivery and none for dementia. There are few healthcare facilities at central and provincial levels, mainly located in the three biggest cities of Hanoi, Ho Chi Minh and Danang, providing services for people with dementia. There is limited training in dementia diagnosis and management for health professionals.

Conclusion

Developing a national dementia plan, including transforming the current healthcare services to better cope with rapid population ageing and dementia disease is urgently needed in Vietnam. Integrating dementia services into existing health and social services for the elderly and the disabled, making use of the extensive primary healthcare system in detection, early interventions, management and support for people with dementia at community level are strategic solutions to deal with dementia in a sustainable way. To this end, a whole‐system approach in transformation and operation with implementing a patient centred care model is necessary.
Pimavanserin and concomitant anti‐dementia medication use in patients with neurodegenerative and/or neurovascular disorders: Safety outcomes from pooled clinical data and the HARMONY study
Authors: Foff Erin P. , McEvoy Bradley , Skoog Benjamin , Demos George
Published: December 2021

Background

Pimavanserin, a selective serotonin receptor modulating agent, is approved to treat hallucinations and delusions associated with Parkinson’s disease psychosis and is being investigated for the treatment of hallucinations and delusions associated with dementia‐related psychosis (DRP). Many DRP patients also receive concomitant antidementia medication (cADM), such as acetylcholinesterase inhibitors or memantine. We evaluated the tolerability of cADM use in pimavanserin‐treated patients with neurologic disease.

Methods

Treatment‐emergent adverse events (TEAEs) were examined using pooled data from 8 double‐blind, placebo‐controlled, parallel‐group studies of patients with neurodegenerative and/or neurovascular disease (collectively, NDD) who received pimavanserin 34 mg (N=580) or placebo (N=649) once daily and data from HARMONY, the phase 3 randomized discontinuation study of pimavanserin for DRP. HARMONY included a 12‐week open‐label (OL) period (N=392) followed by a 26‐week double‐blind (DB) period where subjects were randomized to continue pimavanserin treatment (N=105) or switch to placebo (N=112).

Results

In the pooled NDD population, 291 (50.2%) pimavanserin‐treated and 305 (47.0%) placebo‐treated patients had cADM use. Those with cADM use had lower rates of TEAEs (pimavanserin: 51.2%, placebo: 52.1%) vs those without (pimavanserin: 56.7%, placebo: 59.6%). Rates of serious TEAEs were also similar in patients treated with cADM (pimavanserin: 6.9%, placebo: 4.6%) vs those without cADM (pimavanserin: 7.3%, placebo: 4.1%). In the OL period of HARMONY, 273 (69.6%) patients had cADM use; their rates of TEAEs (with cADM: 32.2%, without cADM: 45.4%) and serious TEAEs (with cADM: 3.3%; without cADM: 9.2%) were similar to patients without. In the DB period, 81 (77.1%) pimavanserin‐treated and 72 (64.3%) placebo‐treated patients used cADM. DB patients with cADM use exhibited rates of TEAEs (pimavanserin: 37.0%, placebo: 31.9%) and serious TEAEs (pimavanserin: 3.7%, placebo: 4.2%) similar to patients without (TEAEs, pimavanserin: 54.2%, placebo: 45.0%; serious TEAEs, pimavanserin: 8.3%, placebo: 2.5%).

Conclusions

Patients with NDD receiving pimavanserin in clinical trials commonly took cADMs. There was no evidence that concomitant pimavanserin use resulted in a differential TEAE or serious TEAE profile in patients taking antidementia medications.
Depressive symptoms in patients referred for clinical amyloid PET imaging
Authors: Loreto Flavia , Fitzgerald Anna , Golemme Mara , Win Zarni , Patel Neva , Gunning Stephen , Gontsarova Anastasia , Kennedy Angus , Edison Paul , Carswell Christopher J , Perry Richard J , Malhotra Paresh A
Published: December 2021

Background

The clinical use of amyloid‐PET imaging (API) is guided by a set of published appropriate use criteria (Johnson et al., 2013). Patients meeting these criteria have suspected Alzheimer’s Disease (AD) accompanied by an atypical clinical presentation leading to substantial diagnostic uncertainty. Previous large‐cohort studies have investigated this clinical population from a diagnostic standpoint, looking at the impact of using amyloid‐PET to elucidate the aetiology of impairment. However, data concerning their clinical phenotypes is lacking. In this study, we investigated the prevalence of depression and its association with Alzheimer’s pathology in Memory Clinic patients who received clinical API.

Method

We reviewed the clinical records of 185 older adults (mean age 67.09±9.35, 49% females) who were assessed in our Clinic between January 2017 and June 2019 and received API. Referral to amyloid‐PET followed a multidisciplinary meeting and was in line with appropriate use criteria. Patients were categorised as ‘D+’, with history of depression, if they had received a previous depression diagnosis and/or if they had a history of depressive symptoms. Overall depression prevalence was compared with published cohort data. Amyloid‐PET results (positive versus negative) were compared between the D+ and the D‐ (without history of depression) groups. In D+ patients, we determined the onset and status of depressive symptoms.

Result

Of 185 patients, 98 (53%) had a history of depression. Of these, 89 individuals had ongoing symptoms at the time of referral to our Clinic and 59 of them were on antidepressants. The mean age of depression onset was 58.25(±12.25) years. Depression prevalence in this cohort was considerably higher than that generally seen in memory clinics (20%; Knapskog et al., 2014) and in healthy older adults (19%; McDougall et al.,2017). Depression history was not associated with amyloid‐PET results (%positive: D+ 39.8%, D‐ 50.6%, χ2(1)=2.16 p=.14), age (mean±SD: D+ 66.47±9.03 years, D‐ 67.79±9.71 years, t(183)=‐.95 p=.342), or sex (%female: D+ 44.9%, D‐ 52.9%, χ2(1)=.1.17 p=.304).

Conclusion

Depression prevalence is high in patients referred for clinical amyloid‐PET imaging and is independent of the presence or absence of Alzheimer’s pathology. Depression may be one of the key contributors to diagnostic uncertainty in this group.
Associations between REM‐sleep EEG spectral power, the cholinergic basal forebrain volume and episodic memory in ageing
Authors: André Claire , Martineau‐Dussault Marie‐Ève , Daneault Véronique , Blais Hélène , Lorrain Dominique , Hudon Carol , Bastien Célyne , Petit Dominique , Lafrenière Alexandre , Legault Julie , Martinez Guillermo E. , Thompson Cynthia , Montplaisir Jacques , Gosselin Nadia , Carrier Julie
Published: December 2021

Background

Our research team has demonstrated that quantitative electroencephalography (qEEG) slowing during rapid‐eye movement (REM) sleep is a more powerful tool to discriminate patients with mild cognitive impairment (MCI) or Alzheimer Disease (AD) from healthy controls than waking EEG. Cortical activation during REM sleep highly depends on the cholinergic basal forebrain system (BFCS) neurons, while other neuronal systems are less active compared to wakefulness. However, the BFCS degenerates early in AD. Here, we tested the hypothesis that REM sleep EEG activity could be strongly associated with neurodegeneration of the BFCS, before the onset of dementia.

Method

134 participants (mean age 68.45 ± 7.8 years; 52 women; 61 with MCI) underwent a polysomnography, structural magnetic resonance imaging, and a neuropsychological evaluation. T1‐weighted images were preprocessed using CAT12 and the DARTEL algorithm, and the JuBrain Anatomy Toolbox was used to extract bilateral BFCS volumes (i.e., Ch1‐2‐3, Ch4 and total volume). Based on prior evidence, theta (4‐8Hz) and alpha (8‐13Hz) absolute EEG power during REM sleep were computed on temporal electrodes (T3‐T4‐T5‐T6). A composite episodic memory score was calculated as the mean of Z‐scores obtained on the Rey Auditory Verbal Learning Test immediate and delayed free recalls. Multiple regressions were performed between (i) spectral power values or (ii) episodic memory performance, and basal forebrain volumes controlling for age, sex, the apnea‐hypopnea index, and the total intracranial volume. Complementary analyses were performed by stratifying the cohort by sex.

Result

Both Ch4 (r=0.24, p=0.006) and total BFCS (r=0.25, p=0.005) volumes were positively associated with episodic memory performance. Ch4 (r=‐0.21; p=0.025) and total BFCS (r=‐0.22; p=0.02) volumes were negatively associated with temporal theta power. Moreover, total BFCS (r=‐0.22; p=0.023) volumes were negatively associated with temporal alpha power. Sex‐stratified analyses revealed that the associations between BFCS volumes, REM‐sleep spectral power and episodic memory were significant in women, but not in men.

Conclusion

These results confirmed that cortical activation during REM sleep is sensitive to volume loss in the BFCS, a cholinergic region known to degenerate early in AD. Why this association was only observed in women is intriguing and will need further investigation.
Subjective social status, objective socioeconomic status, and memory aging
Authors: Chen Xi , Varghese Leah , Jagust William J.
Published: December 2021

Background

Memory aging is a heterogeneous process. Many research efforts have been made to explore what might “slow down” memory aging. The present study examined how subjective social status and objective socioeconomic status may be protective for memory aging in normal adults.

Method

We recruited 272 participants (aged 20‐70 yrs old) online using MTurk, and measured their memory performance using a newly developed task that examines multiple domains of visual memory. During this task (Fig. 1), participants viewed and made judgements of pictures depicting an object in a scene and later completed a surprise recognition test where they indicated if they remember seeing the identical picture earlier. In the recognition test, some pictures were the exact pictures presented earlier; some were lures that had a different object, a different scene, or a different spatial relation of the object to the scene; and some were completely new pictures. We measured memory performance based on participant’s response accuracy. We additionally collected information on participants’ subjective social status (using the MacArthur Scale of Subjective Social Status), education, occupation class, and individual and household income.

Result

As expected, increasing age was related to worse memory performance. Importantly, subjective social status moderated the aging effect on memory: people who rated their social status to be higher (top 40%) did not show the typical age‐related decrease in memory (Fig. 2a). Higher household income was also associated with slower memory aging: people who reported having higher household income (>$75,000) did not show an age‐related memory decrease (Fig. 2b). Education and occupation, however, did not moderate memory aging. Finally, we found the moderating effects of subjective social status and income were interactive: higher income was associated with less memory aging in people with low subjective social status, while higher subjective social status was associated with less memory aging for people with low income (Fig. 2c).

Conclusion

Subjective beliefs of having a high social position and objectively having a high income are two factors that may “slow down” memory aging. They work together in a way where one protects when the other fails to do so.