bluuebunny/crossref_metadata_2025 huggingface dataset:
Boswellic acids (K‐Vie™) improves clinical cognitive scores and reduces systemic inflammation in patients with mild to moderate Alzheimer’s disease.
Authors: Karima Saeed , Aghamollaii Vajiheh , Tafakhori Abbas , Baram Somayeh Mahmoodi , Balenci Laurent , Lanctôt Krista L. , Kiss Alexander , Mahdavi Meisam , Rajaei Shima , Shateri Somayeh , Mokhtari Farzad , Fotouhi Akbar , Riazi Ali
Published: December 2022

Background

Alzheimer’s disease (AD) remains an incurable neurodegenerative disorder. Neuroinflammation has been now recognized as an important player in the pathogenesis of AD. We conducted a clinical trial to measure whether boswellic acids (K‐Vie™, an enriched Boswellia extract) can improve cognitive and neuropsychiatric symptoms while reducing inflammation in patients with AD.

Method

We conducted a placebo‐controlled clinical trial including a total of 85 patients with mild‐to‐moderate (based on MMSE) Alzheimer’s disease randomized to Boswellia (n = 43) and placebo (n = 42) groups. The treatment doses were 400 mg K‐Vie™ capsule, thrice a day (1200 mg/day), versus matching placebo.

Result

Of 85 patients, 43 were assigned to Boswellia and 42 to the placebo group. There were 8 dropouts. The median age of study participants was ∼71 (range, 63‐85) for the Boswellia and ∼70 (range, 61‐81) for the placebo group with 54.5% females and 45.5% males. After 6 months of treatment, there was a significant increase of the MMSE scores with a 1.7 (df = 39, 95% CI 1.2 to 2.1) unit in the Boswellia group compared to ‐1.4 (df = 36, 95% CI ‐2.0 to ‐0.9) unit decrease in the placebo group. There was also a significant decrease of the CDR‐SOB scores in the boswellia group with ‐0.8 (df = 39, 95% CI ‐1.1 to ‐0.6) unit difference, whereas the placebo group saw a 0.8 (df = 36, 95% CI 0.4 to 1.2) unit increase from baseline to 6 months. The analysis of neuropsychiatric symptoms (NPI‐Q) revealed a significant ‐3.4 (df = 27, 95% CI ‐6.1 to ‐0.8) unit decrease, whereas the placebo group did not show a significant change (p = 0.08) (df = 23, 95% CI ‐0.4 to 6.9). Patients receiving Boswellia showed a significant decrease as compared to placebo in plasma levels of several key pro‐inflammatory cytokines including IL‐6 (F(1,38) = 71.1, p<0.0001), TNF‐α (F(1,35) = 14.8, p = 0.0005), and IL‐1α (F(1,38) = 33.4, p<0.0001) as well as a significant increase in the plasma level of amyloid‐β42/amyloid‐β40 ratio (F(1,36) = 19.3, p<0.0001). No serious adverse events were observed during the trial.

Conclusion

This study suggests that a reduction of systemic inflammatory biomarkers correlates with improvement in brain and cognitive function. Decreasing inflammation may represent a novel avenue to effectively treat AD.
A longitudinal investigation of physical and cognitive activities and the outcome of trajectories of AD neuroimaging biomarkers: The Mayo Clinic Study of Aging
Authors: Krell‐Roesch Janina , Syrjanen Jeremy A. , Bezold Jelena , Barisch‐Fritz Bettina , Trautwein Sandra , Woll Alexander , Stokin Gorazd B. , Vemuri Prashanthi , Eugene Scharf L. , Fields Julie A. , Kremers Walter K. , Lowe Val J. , Jack Clifford R. , Knopman David S. , Petersen Ronald C. , Vassilaki Maria , Geda Yonas E.
Published: December 2022

Background

Physical and cognitive activities are associated with decreased risk of mild cognitive impairment and dementia. However, the longitudinal associations between physical and cognitive activities with trajectories of Alzheimer’s disease (AD) neuroimaging biomarkers among older adults free of dementia remain unclear.

Method

We conducted a longitudinal study derived from the population‐based Mayo Clinic Study of Aging, including individuals aged ≥ 50 years who were free of dementia. Participants had information on physical and cognitive activity engagement in midlife (ages 30‐45 for participants aged 50‐69; ages 50‐65 for participants aged ≥ 70) and late‐life (12 months prior to baseline assessment), and AD biomarker assessments. We calculated linear mixed‐effect models to examine the association between baseline physical and cognitive activity composite scores for mid‐ and late‐life, and trajectories for individual yearly change in amyloid deposition (measured by PiB‐PET), tau burden (measured by Tau‐PET), regional glucose hypometabolism (measured by FDG‐PET), cortical thickness (measured by MRI), and white matter hyper intensities (WMH, measured by FLAIR‐MRI). The models were adjusted for age, sex, and APOE ɛ4 carrier status.

Result

The sample included 2755 persons (52% males; 2462 cognitively unimpaired, 293 with MCI). The mean [SD] age was 72.7 [9.8] years; 774 participants were APOE ɛ4 carriers. Although, overall, participants showed an increase in amyloid deposition, tau burden, WMH, and a decrease in glucose metabolism and cortical thickness over time, those with higher late‐life physical activity experienced less pronounced increase in Tau‐PET SUVR over time [estimate for late‐life physical activity with time interaction: ‐0.002; 95% CI ‐0.004, ‐0.000; p = 0.034]. In addition, participants with higher cognitive activities in midlife [est. for midlife cognitive activity with time interaction: 0.001; 95% CI 0.000, 0.003; p = 0.026] and late‐life [est. for late‐life cognitive activity with time interaction 0.002; 95% CI 0.001, 0.003; p = 0.005] had less pronounced decrease in FDG‐PET SUVR over time. There were no further significant interactions.

Conclusion

Preliminary findings suggest significant associations between 1) late‐life physical activity and less tauopathy, and 2) cognitive activities in mid‐ and late‐life with less synaptic dysfunction over time. Further research is needed to validate study findings.
WVE‐005, a stereopure antisense oligonucleotide for MAPT silencing in tauopathies
Authors: DaleMaguire ElenaAbbie , Guo Lankai , Byrne Michael , Cannon Megan , Taborn Kris , Prakasha Priyanka Shiva , Longo Kenneth , Iwamoto Naoki , Kandasamy Pachamuthu , Shimizu Mamoru , Shum Pochi , Ranade Ashwini , Iyer Raghuvaran , Bowman Keith , Yang Hailin , Yin Yuan Benny , Liu Fangjun , Mohapatra Susovan , Macovei Lilia , Patil Saurabh , Lansita Janice , Hu Xiao Shelley , Smith Karen , Goyal Jaya , Narayanan Padma , Rhodes Ken , Panzara Michael , Vargeese Chandra
Published: December 2022

Background: Tau is a neuronal scaffolding protein which aggregates intracellularly upon hyperphosphorylation to form neurofibrillary tangles (NFT). NFTs are a hallmark of various microtubule associated protein tau (MAPT)‐associated neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia, and progressive supranuclear palsy. Currently, there is no approved treatment targeting Tau pathology, nor any other disease‐modifying therapy for these diseases. Wave Life Sciences has developed a stereopure antisense oligonucleotide to reduce MAPT expression in patients with MAPT‐associated neurodegenerative diseases.

Method: Using Wave’s proprietary PRISM platform, we designed and screened stereopure oligonucleotides targeting MAPT in vitro and identified a lead sequence. PN chemistry was applied to the lead sequence in subsequent studies to further improve pharmacological properties. In vitro target engagement was measured in human iCell neurons after treatment with Wave’s oligonucleotide, WVE‐005, or a published reference stereorandom oligonucleotide under gymnotic conditions. For in vivo analysis, transgenic mice received a single dose of 12.5, 25, 50, or 100µg oligonucleotide, and target engagement was measured after 4 weeks. To measure duration, transgenic mice received a single 100µg ICV dose and target engagement was tracked over 6 months. Finally, oligonucleotides were tested in non‐human primates (NHP) in a 12mg single‐dose intrathecal (IT) study. MAPT mRNA levels were quantified by qPCR, and intracellular distribution was evaluated by ViewRNA.

Result: WVE‐005 showed dose‐dependent silencing of MAPT mRNA in iPSC‐derived neurons with an IC50 of 84nM. In a dose‐response study, 12.5µg and 25µg WVE‐005 led to 50% knockdown after 4 weeks in hippocampus and cortex, respectively, in transgenic mice. WVE‐005 led to >77% MAPT mRNA knockdown at 12 weeks post 100µg dosing, with knockdown of approximately 50% persisting 6 months post‐injection. In NHPs, WVE‐005 showed improved distribution and potency compared to non‐PN oligonucleotide with the same sequence. WVE‐005 decreased MAPT expression across NHP brain regions 28 days post‐single dose much greater than the non‐PN oligonucleotide and was detected in neuronal and glial cells.

Conclusion: WVE‐005 potently and durably decreased MAPT mRNA expression in vitro and in multiple animal models, including throughout CNS upon IT administration in NHPs. These data support continued evaluation of WVE‐005 as a potential therapeutic for MAPT‐associated neurodegenerative diseases.
Illusory responses across the Alzheimer’s disease spectrum and Lewy body disease spectrum
Authors: Shahid Marian , Rawls Ashley , Ramirez Veronica , Ryman Sephira , Santini Veronica E , Yang Laurice , Sha Sharon , Hall Jacob N , Montine Thomas J. , Lin Amy , Henderson Victor , Cholerton Brenna , Yutsis Maya , Poston Kathleen L
Published: December 2022

Background

Pareidolias are specific illusions of faces and objects perceived in formless visual stimuli. In studies using a noise pareidolia task in patients with clinical dementia, Dementia with Lewy Bodies patients report more illusory responses than Alzheimer’s disease patients, which correlates with severity of visual hallucinations (Yokoi et al., 2014). However, it is unknown whether illusory responses occur in earlier stages of disease or in non‐hallucinating patients across the Lewy body disease (LBD) spectrum, such as Parkinson’s Disease with and without cognitive impairment.

Method

We studied the National Alzheimer’s Coordinating Center Noise Pareidolia Task‐Short Form from the LBD Module in 300 participants from the Stanford Alzheimer’s Disease Research Center and Pacific Udall Center who completed comprehensive motor and cognitive assessments with consensus diagnostic adjudication. We included 51 Alzheimer’s disease‐spectrum (AD‐s), 38 LBD with cognitive impairment (LB‐abnlCog), 65 LBD with no cognitive impairment (LB‐nlCog), and 146 Controls. Pairwise between‐group comparisons examined the impact of diagnosis on number of illusory responses. Ordinal regression analysis compared the number of illusory responses on the Noise Pareidolia Task across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions.

Result

See Table 1 for diagnosis group demographic characteristics. LB‐abnlCog were more than 10 times more likely than Controls and about 4–5 times more likely than AD‐s and LB‐nlCog participants to endorse illusory responses. The probability of endorsing one or more illusory response was 61% in the LB‐abnlCog group, compared to 26% in AD‐s, 25% in LB‐nlCog and 12% in Control participants (Figure 1). In LBD participants without hallucinations or delusions, 52% of those with mild cognitive impairment and 67% with dementia endorsed at least one illusory response.

Conclusion

Illusory responses are common in cognitively impaired LBD patients, including those without any reported psychosis. The Noise Pareidolia Task does not distinguish between Alzheimer’s disease and Lewy body patients until there is measurable cognitive impairment in the LBD patients, suggesting that early, unobtrusive pareidolias might arise in conjunction with cognitive decline in LBD.
Educational Quality and Incident All‐Cause Dementia: Black‐White Differences
Authors: Soh Yenee , Mayeda Elizabeth Rose , Peterson Rachel L. , Eng Chloe W. , Quesenberry Charles P. , Whitmer Rachel A. , Glymour M. Maria , Gilsanz Paola
Published: December 2022

Background

Measurement of education via years of schooling may not be commensurate across racial and ethnic groups because of disparities in educational quality. We examine state‐level administrative school quality data and incident all‐cause dementia among Kaiser Permanente Northern California members who participated in a midlife survey and were aged 65 years or older at the start of follow‐up (1997).

Methods

We obtained educational attainment and birth state from surveys administered during 1964‐1973. We linked birth state with state‐level school quality measures (student‐teacher ratio, attendance rates, term length), categorized into tertiles using the overall sample. We obtained sex, race, and incident dementia diagnoses during follow‐up (1997‐2018) from electronic health records. Using race‐stratified Cox proportional hazards models (age as timescale), we estimated associations between each educational quality measure and dementia risk, adjusting for sex, birth region and educational attainment.

Result

Among 39,632 participants, 17% identified as Black, 44% reported less than high school education, and 7,206 individuals were diagnosed with dementia (mean follow‐up 13.5 years) (Table 1). Average educational quality was lower among Black participants (Table 1). Higher attendance rates and longer term length were associated with lower dementia risk among both racial groups (Figure 1, Table 2). Among Black participants, for example, highest versus lowest attendance rate tertile was associated with 50% lower risk (adjusted hazard ratio [HR]: 0.50, 95% confidence interval [CI]: 0.38‐0.67). Lower student‐teacher ratio was associated with lower risk only among White participants. The association between higher educational quality and lower dementia risk was stronger among Black than White participants for attendance rates and term length (race‐school quality interaction term p‐value: 0.05 and 0.03, respectively), but not significantly different for student‐teacher ratio.

Conclusion

In both Black and White participants, higher school quality is associated with lower risk of incident dementia, even after adjusting for educational attainment. The associations were stronger among Black participants for attendance rates and term length. Educational disparities may partially be explained by lower average educational quality among Black participants, limiting its protective effects.
Baseline White Matter Neuroinflammation Predicts Cognitive Decline in Alzheimer Disease
Authors: Wang Qing , Wang Wenshang , Schindler Suzanne E. , McKay Nicole S. , Chen Gengsheng , Liu Jingxia , Wang Sicheng , Sun Zhexian , Hassenstab Jason J. , Fagan Anne M. , Morris John C. , Wang Yong , Benzinger Tammie L.S.
Published: December 2022

Background

Neuroinflammation, an intrinsic immune response of the nervous system, is important in an early phase of Alzheimer Disease (AD) pathogenesis. However, it is largely unclear how neuroinflammation promotes the clinical progression of AD. Extracellular water edema (ECW) from Neuro‐inflammation imaging (NII), a diffusion‐based MRI approach for neuroinflammation, has been utilized to asses white matter (WM) neuroinflammation in AD. This study aims to investigate the relationship between WM neuroinflammation and longitudinal cognitive changes in AD.

Method

This study included 286 participants who were enrolled in ongoing research at the Knight ADRC at Washington University in Saint Louis. The CSF levels of Aβ42/Aβ40 and ptau181 measured with the automated Lumipulse platform were used to categorize the participants as being positive or negative amyloid (A) and tau (T), respectively (Table 1). As measures of cognitive performance, the Knight ADRC Preclinical Alzheimer Cognitive Composite (Knight ADRC‐PACC) and a Global composite score were employed for each individual. The rates of change of cognitive measures were calculated for each individual. The NII was acquired with a multi‐b value scheme (bmax =1400s/mm2 and 25 directions). The total WM neuroinflammation (NII‐ECW) was obtained using the TBSS (http://www.fmrib.ox.ac.uk/fsl) based WM skeleton. Randomise in FSL was utilized to examine voxel‐wise relationships between NII‐ECW and the rate of change of cognitive measures. Non‐parametric Kruskal‐Wallis and Chi‐square tests were employed for comparing continuous and categorical variables of the participants’ demographics, respectively. The group differences of NII‐ECW were tested using one‐way ANOVA. All statistical tests were conducted in R (R Core Team, 2020). Age, sex, and APOE ε4 carrier status were adjusted as covariates.

Result

Table 1 summarizes demographic data. When compared to the A‐T‐ group, the A+T+CDR0 and A+T+CDR0.5 groups had higher NII‐ECW (Figure 1). When the A+T+CDR1 group was compared to the other groups, there was no group difference in NII‐ECW. There were substantial negative associations between the NII‐ECW and the rates of change of cognitive measures in the widespread WM regions (Figure 2).

Conclusion

Our data suggest that neuroinflammation increases early in preclinical AD and decreases later in the disease. Furthermore, baseline neuroinflammation as measured by NII‐ECW predicts cognitive decline in AD.
Development of retinal biomarkers for Alzheimer's disease
Authors: Leuenberger Rebecca C.T. , Verbraak Frank D. , Twisk Jos W.R. , de Ruyter Frederique J. Hart , Hoozemans Jeroen J.M. , de Boer Johannes , Bouwman Femke H.
Published: December 2022

Background

The retina has received increasing intention as possible non‐invasive diagnostic biomarker for (preclinical) Alzheimer’s disease (AD). Several studies suggest changes in retinal layer thickness or vasculature in patients with AD. Here, we aim to discriminate (preclinical) Alzheimer’s disease from controls using three retinal imaging modalities in a multimodal prediction model.

Method

We used images of 103 controls, 26 clinical AD cases, and 13 preclinical AD cases. Control subjects were cognitively healthy with a negative amyloid‐PET. Preclinical AD participants were defined as cognitively healthy subjects with a positive amyloid‐PET. The 26 clinical AD participants were recruited from the Amsterdam Dementia Cohort and fulfilled the NIA‐AA criteria with evidence of amyloid pathology based on amyloid‐PET or cerebrospinal fluid. Participants underwent three imaging modalities (Optical Coherence Tomography, Optical Coherence Tomography Angiography, fundus photography) and ophthalmological examinations to exclude ophthalmological comorbidities that could influence retinal parameters. First, we performed a multivariable logistic regression analyses per imaging modality, adjusted for age and sex, using all parameters provided by each device. Second, we created an explorative multimodal prediction model including the best performing variable per imaging modality, using the following parameters: retinal nerve fiber layer inner ring, macular vessel density outer ring and the central retinal vein equivalent (CRVE). We used Receiver Operating Characteristic (ROC) curves to test the overall predictive accuracy.

Result

The final explorative multimodal prediction model showed an acceptable predictive accuracy in discriminating AD from controls with an area under the receiving operating characteristic curve (AUC) of 0.987, and less so in the discrimination between preclinical AD and controls with an AUC of 0.775. However, with differences in the way the coefficients of identical parameters contributed to make the differentiation between AD and controls and preclinical AD and controls.

Conclusion

Despite of a relatively small sample size, our multimodal retinal imaging prediction model seems promising in discriminating between AD versus controls, and preclinical AD versus controls. We found that two parameters, the macular vessel density outer ring and CRVE behaved differently in AD cases compared to preclinical AD cases. More prospective studies with larger sample sizes are needed to confirm these findings.
A Million Veteran Program GWAS of Alzheimer’s Disease and Related Dementias in African Americans Identifies Multiple Genome‐Wide Significant Dementia Risk Loci
Authors: Sherva Richard , Zhang Rui , Farrer Lindsay A. , Sahelijo Nathan , Jun Gyungah R , Anglin Tori , Chanfreau Catherine , Cho Kelly , Fonda Jennifer , Gaziano J. Michael , Harrington Kelly , Ho Yuk‐Lam , Kremen William S. , Litkowski Elizabeth M , Lynch Julie , Neale Zoe , Roussos Panos , Marra David E , Mez Jesse B. , Miller Mark , Salat David H , Tsuang Debby W , Wolf Erika , Zeng Qing , Panizzon Matthew S. , Merritt Victoria , Hauger Richard L. , Logue Mark W.
Published: December 2022

Background

While genome wide association studies (GWASs) of Alzheimer’s Disease (AD) in European ancestry cohorts (EUR) have identified >70 potentially independent AD risk loci, progress in non‐European populations has lagged. In this study, data from US Veterans of African ancestry (AFR) from the Million Veteran Program (MVP) biorepository were used to identify genetic factors associated with AD and related dementias (ADRD).

Method

Using the VA electronic medical record, 4,012 AFR ADRD cases (algorithm includes codes for AD and dementias such as vascular dementia) and 18,435 dementia‐free AFR controls were identified for inclusion in the GWAS. A GWAS was also performed using proxy dementia based on survey‐reported AFR participant parental history of AD or other dementia that included 4,385 maternal cases, 2,256 paternal cases, and 45,970 controls. Meta‐analysis of the case control and proxy results for was performed and then subsequently combined with results from a AFR AD GWAS conducted by the Alzheimer Disease Genetics Consortium (ADGC; Kunkle et al., 2021).

Result

The AFR MVP GWAS (case‐control + proxy) yielded genome‐wide significant associations with several loci including APOE (p=2.48x10‐101), ROBO1 (rs11919682, p=1.63x10‐8), and RP11‐340A13.2 (rs148433063, p=8.56x10‐9. The ROBO1 and RP11‐240A13.2 SNPs were not replicated in the ADGC sample (missing or not significant). The meta‐analysis of MVP and ADGC GWAS results (Table 1) additionally identified genome significant SNPs near known AD risk genes TREM2 (rs73427293, p=2.95x10‐9), CD2AP (rs7738720, p=1.14x10‐9), and ABCA7 (rs73505251, p=3.26x10‐10). Comparison of expression of genes near variants with suggestive evidence of association (p<5x10‐7) in the brains of EUR AD cases and controls from Framingham Heart Study, Religious Orders Study/Rush Memory and Aging Project, Mayo‐Mount Sinai Brain Bank, and Boston University Brain Bank (Panitch et al.) identified several differentially expressed genes including EML6.

Conclusion

The AFR dementia GWAS presented here is the largest to date. It increased the number of genome wide significant common‐variant dementia loci reported in AFR cohorts from two to six, including genes previously implicated in EUR cohorts. Increasing representation of AFRs is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.
The Association of Sleep Duration and Sleep Efficiency with Amyloid β Accumulation Among Cognitively Healthy Later Life Adults: A Systematic Review
Authors: Moon Chooza , Schneider Aaron , Zhang Meina , Cho Young‐Eun , Dang Hellen , Vu Kelly H
Published: December 2022

Background

Amyloid β(Aβ) accumulation is a hallmark of the progressive neurodegenerative Alzheimer’s Disease (AD). Disruptions in sleep beyond aging are found to be risk factors of developing AD because sleep may involves in Aβ level regulations, neurotoxin clearance, or inflammation process. Sleep disruptions can be defined by shorter sleep duration and lower sleep efficiency. This systematic review examines how sleep duration and efficiency are associated with amyloid deposition in later life adults.

Method

We screened 3,122 published articles searched from electronic databases (i.e., PubMed, CINAHL, Embase, and PsycINFO) and used 14 articles for the qualitative synthesis. All articles met the eligibility criteria including published articles that contain sleep duration and efficiency measure, Aβ measure, human studies with cognitively normal older adults who are 50 and above.

Result

Studies were conducted in the United States, Italy, South Korea, China, and Australia. Of the 14 studies included, 12 used a cross‐sectional design and 2 used a longitudinal design. Sample sizes ranged from 13 to 4,772. Ages of the samples ranged from 50 to 85. Studies measured Aβ using cerebrospinal fluid, serum, and Positron Emission Tomography (PET) scans with two different tracers: C‐labeled Pittsburgh compound B or fluorine 18–labeled (18F). Sleep duration and efficiency were subjectively measured using interviews and questionnaires, or objective measures, such as polysomnography or actigraphy. Studies accounted for demographic and lifestyle factors in their analyses, such as age, sex, family history, sleep, habitual alcohol consumption, slow wave sleep, apnea hypopnea index, exercise, fasting glucose, and triglycerides. Only 3 of the 14 studies indicated that sleep duration was associated with Aβ accumulation, and 4 of the studies revealed that sleep efficiency was associated with Aβ accumulation.

Conclusion

This review suggests that previous studies have provided mixed evidence regarding the relationship between sleep duration and Aβ or the relationship between sleep efficiency and Aβ. Not all studies used a sufficient sample size or a comprehensive measurement of sleep. These results indicate the need for more future studies using a longitudinal design, comprehensive sleep measure, and larger sample sizes to advance understanding the relationship between sleep and Aβ.
Loss of large dendritic spines during normal aging is mediated by alterations in discrete protein networks within the precuneus
Authors: Krivinko Josh , Sui Zhiyu , Happe Cassandra , Hensler Christopher , McKinney Brandon , Newman Jason , Ding Ying , MacDonald Matthew , Sweet Robert
Published: December 2022

Background

Loss of dendritic spine density in neocortical areas is a well‐known correlate of cognitive decline in Alzheimer Disease (AD), while preservation of dendritic spines in subjects containing AD‐related pathology is associated with cognitive resilience. Because normal aging is itself associated with dendritic spine loss, identifying upstream mediators of dendritic spine loss may provide an opportunity to develop targeted pharmacotherapies which enhance cognitive resilience and protect against dementia onset. We therefore quantified dendritic spine density and the abundance of over 5000 proteins in the precuneus, a cortical region that is selectively vulnerable early in AD progression.

Method

The right precuneus was isolated postmortem from 98 subjects, ages 20‐96 years, none of whom had a documented neurocognitive disorder. Quantitative immunohistochemistry and spinning disk microscopy were used to estimate dendritic spine density by detecting colocalization of spinophilin and filamentous actin. Gray matter was biochemically fractioned into cellular homogenate and synaptosome fractions, and protein abundance was quantified by liquid chromatography/tandem mass tag mass spectrometry. Proteins were assembled into correlated networks using Weighted Gene Co‐expression Network Analysis (WGCNA), and a statistical mediation analysis was used to identify protein networks which mediate the effect of age on dendritic spine density. WebGestalt was used to identify enrichment for gene ontology terms for protein networks relative to a background of all proteins detected in homogenate.

Result

The density of large dendritic spines exhibited a negative correlation with increasing age (Pearson R= ‐0.36, p<0.001) (Figure 1). A total of 1839 of 5032 proteins detected in cellular homogenate and 914 of 4754 proteins detected in synaptosomes was significantly correlated with age (q<0.05). Proteins segregated into 19 network modules, five of which significantly mediated the effect of age on dendritic spine density. The modules were enriched for gene ontology terms including “positive regulation of excitatory postsynaptic potential” (enrichment ratio=11.0, p=0.034), “neurotransmitter transport” (enrichment ratio=3.9, p=0.003) and “myelination” (enrichment ratio=21.5, p=<0.001).

Conclusion

Density of large dendritic spines declines linearly with age within the precuneus. Network analysis revealed a novel role for myelination by oligodendrocytes in spine loss, identifying a potential target to increase cognitive resilience during aging.
Support for Dementia Care Partners using Telehealth: Tele‐STELLA Phase 1
Authors: Lindauer Allison , Gothard Sarah , Boardman Charles , Smith Samantha , Mattek Nora , McDaniel Delaney , Bernard Hannah , Tran Leslie , Tadesse Ruth
Published: December 2022

Background

Effective interventions that reduce dementia Care Partner stress and burden are available, but access to them is impeded by barriers such as distance, cost, behavioral symptoms of dementia, stigma and social anxiety. Tele‐STELLA is a multi‐component, videoconference‐based intervention designed to provide easily‐accessible education and support for Care Partners. The goal of this intervention is to diminish the frequency of behavioral symptoms that persons with dementia experience, and Care Partner reactivity to these symptoms. Here we report on the findings of Phase 1 of Tele‐STELLA.

Method

In Tele‐STELLA interventionists meet with Care Partners, via videoconferencing, to identify specific behavioral symptoms of dementia that are distressing for them. The interventionists and Care Partners meet, first individually and then in groups, to address these symptoms using an analytic approach. Care Partners are encouraged to contact each other for support. Prior to, during, and after the 8‐week intervention we collect data on behavioral symptoms (frequency and Care Partner reactivity to the symptoms), depression, and burden using electronically‐administered surveys.

Result

Of the 26 Care Partners who completed 8 weeks of the intervention 19 (70%) were female, average age of 67; 25 (96%) identified as white; 14% lived in a rural area. Burden, as assessed on the Revised Memory and Behavior Problem Checklist, did not change significantly over the 8‐week intervention, nor did scores on depression, grief or quality of life measures. There was no change in behavior frequency, but we did appreciate a significant improvement in Care Partner reactivity to the two personalized target problems they identified (Figures 1 and 2; p<0.01 and p = 0.025, respectively).

Conclusion

Significant improvement was seen in Care Partner reactivity to the specific behavioral problems chosen by the Care Partners. This suggests the intervention is effective when Care Partners work on the personalized problems they identified. The lack of significant improvement on the (depersonalized) surveys may be due to unbiased reporting by Care Partners using electronically‐administered surveys, small sample size, or stabilization of affective symptoms. Phase 1 will inform revisions for the remainder of the study (total n goal = 150).
SAGE‐718 in Patients With Mild Cognitive Impairment or Mild Dementia due to Alzheimer’s Disease: Results From the Phase 2 LUMINARY Study
Authors: Koenig Aaron , Malhotra Shishuka , Wald Jeffrey , Petrillo Jennifer , Paumier Katrina , Johannensen Jason , Li Sigui , Quirk Michael , Freitag Emily , Doherty Jim
Published: December 2022

Background

Cognitive impairment has a deleterious impact on patients with AD and their caregivers; new therapies are needed. SAGE‐718, a novel N‐methyl‐D‐aspartate receptor positive allosteric modulator, is being investigated for the treatment of cognitive impairment in patients with neurodegenerative diseases such as Alzheimer’s disease (AD). The LUMINARY Study is designed to evaluate the safety/tolerability of SAGE‐718 and its effects on cognitive symptoms in patients with AD.

Method

LUMINARY (NCT04602624) is an open‐label, Phase 2 study evaluating SAGE‐718 (3mg QD for 14 days) in patients with AD. Patients (aged 50‐80 years) with Montreal Cognitive Assessment (MoCA) scores of 15‐24 were included. Treatment‐emergent adverse event (TEAE) incidence through Day 28 (primary endpoint), other safety outcomes (secondary endpoints), and cognitive and functional assessments were analyzed.

Result

Twenty‐six patients (69.2% female; mean age 67 years), with a mean±SD MoCA of 20.7±2.61 were enrolled. Most patients (23/26) had a global Clinical Dementia Rating score of 0.5. Eight TEAEs were reported in 7 (26.9%) patients; all were mild/moderate; 6 were treatment related. No serious adverse events or deaths were reported. At Day 14, improvements from baseline were observed on multiple tests of executive functioning (Digit Symbol Substitution, Multitasking, One Touch Stockings, Spatial Working Memory, and 2‐Back tests) and learning and memory (Pattern Recognition Memory and Verbal Recognition Memory tests). Statistically significant MoCA improvement (+2.3 points vs baseline) was observed at Day 28. No changes in attention/psychomotor speed were observed. Functional assessments also captured notable improvement in some patients (Clinical Global Impressions Scales and Amsterdam Instrumental Activities of Daily Living Questionnaire), particularly on items measuring aspects of complex/higher order activities.

Conclusion

In this study, SAGE‐718 was generally well tolerated and associated with cognitive and functional improvements in patients with AD. These results support further investigation of SAGE‐718 for the treatment of cognitive impairment associated with AD and other neurodegenerative diseases.
Concerted alterations of functional connectivity and WM integrity in relationship to early amyloid deposition
Authors: Lorenzini Luigi , Orso Beatrice , García David Vállez , Pontillo Giuseppe , Ingala Silvia , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Chetelat Gael , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Waldman Adam , Ritchie Craig W. , Gispert Juan Domingo , Visser Pieter Jelle , Mutsaerts Henk‐Jan , Tijms Betty M. , Wink Alle Meije , Barkhof Frederik
Published: December 2022

Background

Early amyloid deposition results in functional and structural brain alterations in predementia stages of Alzheimer's disease (AD). However, how early functional and structural brain changes are related to each other remains unclear. Investigating the simultaneous disruptions of functional‐structural brain features within individuals in relation to amyloid deposition may increase our understanding of the neuropathological processes underlying AD.

Method

We included 648 non‐demented participants from the European Prevention for Alzheimer’s Dementia (EPAD) cohort vIMI baseline data release. The cut‐off for cerebrospinal fluid (CSF) amyloid‐β positivity (A+) was defined at <1000pg/mL (Elecsys assay). Functional connectivity was estimated with functional eigenvector centrality (EC) from the resting state functional MRI. White matter (WM) integrity was estimated with fractional anisotropy (FA), computed on diffusion MRI. Both measures were computed at the voxel level within the gray and white matter, respectively. First, we used linear regression models to investigate differences between A+ and A‐ participants within each modality separately, adjusting for age, sex, and site. In the whole group, we performed sparse canonical correlation analysis (sCCA) on functional and structural measures, identifying shared components between the two modalities. Individual sCCA scores were compared between amyloid groups using a generalized linear model (GLM). To evaluate this association in A+ individuals, the same sCCA analysis was performed normalizing the structural and functional matrices using the mean and SD from A‐ participants.

Result

Sample characteristics are provided in Table 1. Differences in voxelwise EC and FA between amyloid groups are shown in Figure 1. In the whole group, sCCA analysis showed that EC in the default mode, executive and cerebellar networks covary with FA in parietal, temporal and cerebellar areas (Figure 2). sCCA projections were differentially expressed according to amyloid status (Table 2). In A+ participants, stronger association of EC in the posterior DMN and cerebellum with FA in the splenium and brainstem were found (Figure 3).

Conclusion

Using a data‐driven multivariate analysis, we identified concerted patterns of functional and structural changes that occur with amyloid deposition in the predementia stage. These results highlight the importance of multimodal assessment for early diagnosis.
Sex Differences in the Clinical Presentation of Prodromal Dementia with Lewy Bodies
Authors: Wyman‐Chick Kathryn A , Bayram Ece , Chiu Shannon Y , Patel Bhavana , Armstrong Melissa J , O'Keefe Lauren R , Cunningham Laura C , Barrett Matthew J
Published: December 2022

Background

Sex is an important biological variable which can influence the prevalence, clinical presentation, and progression of neurodegenerative diseases. Little is known regarding possible sex differences in prodromal dementia with Lewy bodies (DLB).

Method

We analyzed data from the National Alzheimer’s Coordinating Center’s Uniform Data Set (NACC database is funded by NIH U01‐AG016976). Annual visits occurred across 39 past/present Alzheimer’s Disease Research Centers (ADRC) between September 2005 and September 2021. We included non‐demented participants at baseline who were clinically diagnosed with DLB by ADRC staff at a subsequent visit. The presence of motor symptoms, visual hallucinations, REM sleep behavior disorder (RBD), cognitive fluctuations, and neuropsychiatric symptoms were assessed through clinical exam and informant responses 1–2 years prior to DLB diagnosis.

Result

We identified 160 participants with DLB (82.5% male). Male and female groups differed in age and ethnicity (Table 1).There were no differences in education, cognition, functional status, severity of neuropsychiatric symptoms, or number of visits prior to phenoconversion to DLB.

RBD was more prevalent in men (58‐62% vs. 25–36% women). Cognitive fluctuations were also more common among men (33‐40% vs. 6–18% women). Men reported a higher prevalence of visual hallucinations 2‐years prior to dementia diagnosis (23% vs. 6% women), but visual hallucinations were more prevalent in women than men at the first visit with dementia diagnosis (54% women vs. 43% men). Motor slowing and parkinsonian gait were prevalent among both groups; however, tremor and rigidity were more common in men, while postural instability and falls were more frequent in women. Apathy was common in both groups; however, anxiety was more frequent in men, and women had a higher prevalence of depression. (Table 2). The groups did not differ in rates of 1 vs. 2+ core clinical features 1‐year prior to diagnosis (Table 3).

Conclusion

This descriptive analysis appears to indicate there are sex differences in the prodromal presentation of DLB. Men may present with established core features earlier than women. Limitations include lack of pathological confirmation and the number of female and ethno‐racially diverse participants. Understanding differences in clinical presentations may inform diagnostic criteria and therefore improve clinical sensitivity.
Functional Annotations‐Informed Whole Genome Sequence Analysis Identifies Novel Rare Variants for AD in the Alzheimer’s Disease Sequencing Project
Authors: Lee Songmi , Shi Bin , Peloso Gina M , Wang Yanbing , Heard‐Costa Nancy , Lin Honghuang , Pitsillides Achilleas N , Sarnowski Chloé , Boerwinkle Eric , De Jager Philip L , Dupuis Josée , Seshadri Sudha , Wijsman Ellen M , DeStefano Anita L. , Fornage Myriam
Published: December 2022

Background

Incorporating functional annotations improves power to identify rare variants (RV) in the analysis of whole genome sequencing (WGS) association studies. We incorporated Alzheimer’s Disease (AD)‐specific annotations based on partitioning heritability into the variant‐Set Test for Association using Annotation information (STAAR‐O) framework to identify RVs associated with AD in the diverse sample of the Alzheimer’s Disease Sequencing Project (ADSP).

Method

We performed WGS association analyses in a sample of 4,074 individuals (1,668 AD cases; 2,406 controls) sequenced as part of the ADSP Discovery Extension Phase. We first estimated heritability of all single nucleotide variants in functional annotation categories using the GCTA tool embedded in FunSPU. For each annotation category, a global weight was derived based on the partitioned AD heritability. Among weighted functional scores, we selected the top 12 to leverage the most informative functional annotations for incorporation into the STAAR‐O test.2 We performed agnostic region‐based association analysis using sliding windows, defined as 2kb in length with a skip length of 1kb. Association tests were performed with RV (minor allele frequency <1%), adjusting for sex, sequencing center, platform, study, 4 principal components, and a genetic relatedness matrix. Replication of significant associations was carried out in an independent sample of 10,083 individuals (5,717 AD cases, 4,366 controls) sequenced as part of the ADSP Follow‐Up Study and using the same analytical models.

Result

Out of 2.65 million 2‐kb overlapping windows with a total minor allele count >10, two non‐consecutive windows on chromosome 17 were associated with AD (P<5×10−8) (Figures). Both windows associations were replicated in the independent sample (P = 0.003 and 0.016). The top variant of one significant window was rs534148850 (MAF = 0.0005, P = 5.55×10−9) located downstream of PLEKHM1P1, a pseudogene, and MIR4315‐2, a microRNA with predicted targets enriched in apoptosis pathways. The top variant of the other window was rs532055552 (MAF = 0.005, P = 6.20×10−9) located downstream of CEP112, a coiled domain‐containing protein involved in the regulation of gamma‐aminobutyric acid A receptor surface expression.

Conclusion

Incorporating AD‐relevant functional annotations to a powerful RV association framework, we discovered and replicated two novel genetic regions harboring RV associated with AD.
Frequent Cognitive Tests Increase Power for Alzheimer’s Disease Clinical Trials
Authors: Roach Jared C. , Hara Junko , Edens Lance , Rajbhandari Sophiya , Dill Lauren , Romansik Rachel , Rapozo Molly K. , Funk Cory , Jade Kathleen , Merrill David A. , Bramen Jennifer E. , Panos Stella E. , Porter Verna R. , Dye Richelin V. , Ganapathi Aarthi S. , Hodes John F. , Slyapich Colby B. , Glatt Ryan M. , Wong Claudia L. , Fortier Dennis , Shankle William R
Published: December 2022

Background

Many clinical trials use performance‐based cognitive or functional test results as primary outcome measures. As few as two measurements, typically pre‐ and post‐intervention, can be used to define a cognitive trajectory. Increasing the number and frequency of assessments can increase power to test the primary hypothesis. However, increased assessment frequency may be expensive and burdensome to participants and staff. Frequent neuropsychological testing may also introduce a practice effect or learning effect. Trials should be designed with attention to the costs and benefits of more frequent assessments.

Method

We conducted two clinical trials and performed Monte Carlo simulations. The Montreal Cognitive Assessment (MoCA) and the MCI Screen (MCIS) were used to assess cognition; the Functional Assessment Staging Tool (FAST) was used to assess function. In addition to simulated data, we employed data from the Coaching for Cognition in Alzheimer’s (COCOA) and Precision Recommendations for Environmental Variables, Exercise, Nutrition and Training Interventions to Optimize Neurocognition (PREVENTION) Trials.

Result

Effect sizes and measurement variability were similar between the two cognitive screens. More frequent assessments increased power to reject a null hypothesis The major factor driving this improved power was the influence of data from individuals withdrawing from or dropping out of the trial prior to trial end. More frequent testing captured more of the effect of the intervention over time in those individuals, and therefore, increased power for the entire study. The design of the MCIS with rotating word lists facilitated frequent testing without a learning effect. Hypothetically, a more frequently administered assessment might have less precision than a different assessment administered less frequently, and the unit costs of these assessments might differ. Under a wide range of parameters modeled in simulations, the advantages of more frequent testing outweighed decreases in the precision of individual assessments.

Conclusion

More frequent testing should be preferred in clinical trials. Use of shorter and/or remote tests may facilitate such frequency, reduce costs, and increase safety during pandemics. In addition to gains in statistical power, dense measurements have other benefits. They may also reveal non‐linear trajectories and better enable longitudinal analyses such as time dependencies and dose‐response relationships.
Lifestyle and psychosocial changes in Mexican elders during the COVID‐19 pandemic
Authors: Martínez‐Galindo Joyce Graciela , Salinas‐Contreras Rosa Maria , Rocha Ana Sabsil Lopez , Kivipelto Miia , Mangialasche Francesca , Ortiz Ana Luisa Sosa
Published: December 2022

Background

Social and physical activity, the optimal control of cardiovascular disease are important factors to prevent mild cognitive impairment and dementia. During the COVID‐19 pandemic these factors could have negatively been affected, and it is crucial to identify and address such changes.

Nearly two years into the pandemic for COVID‐19 in worldwide, psychological and behavioural consequences have been observed in the population. Social distancing, mobility restraint and quarantine measures have raised concerns about lifestyles and mental health.

Method

This study included 50 urban‐Mexican elders cognitively health but with risk factors for dementia and mild cognitive impairment (age, mean: 72.6 ± 5.1, 54%, with an average schooling of 9.4 ± 4.3 years, 54% women), who responded face to face to a survey designed by the WORLD‐WIDE‐FINGERS‐SARS‐COV‐2 Initiative, which has the objective of measuring the direct and indirect effects of the pandemic in old age, focusing on changes in lifestyle and psychosocial factors, included frequency of physical activity, smoking, alcohol consumption and social activities before and after the pandemic quarantine.

Result

A significant reduction in physical activity and attendance to social meetings was found. Other changes reported included decreased time spent with family, relatives and friends, increased sleep problems and augmented snacking but not increased consumption of fruits and vegetables. Participants also indicated an increased use of the Internet. Interestingly, even if people had less social interaction, they did not report increased feelings of loneliness.

In general, few participants reported changes in physical health (16%) and quality of life (12%) but half of the sample (54%) feel that their memory was poorer than before the pandemic.

Conclusion

In conclusion, we observed changes in lifestyle that can negatively affect mental health, as they involve factors linked to the occurrence of dementia or mild cognitive impairment. Therefore, strategies to mitigate the effects of these risk factors should be planned.