bluuebunny/crossref_metadata_2025 huggingface dataset:
SEMA4D blocking antibody, pepinemab, is a novel potential treatment for neurodegenerative disease: Clinical proof of concept in Phase 2 HD study supports ongoing clinical development in Phase 1/2 AD study
Authors: Fisher Terrence L , Evans Elizabeth E , Boise Megan , Foster Amber , Mishra Vikas , Mallow Crystal L , Smith Ernest S , Leonard John E , Feigin Andrew , Siemers Eric , Walters Kimberly , Sheldon Elizabeth , Turner Scott , Farlow Martin R. , Zauderer Maurice
Published: June 2023

Background

Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin receptors. SEMA4D is upregulated in neurons in response to stress and triggers activation of plexin‐positive astrocytes with concomitant loss of normal astrocyte functions. Drivers of glial cell activation may represent important novel targets to modify progression of neurodegenerative pathology. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in preclinical models, including Huntington’s disease (HD) and Alzheimer’s disease (AD). SIGNAL‐HD (NCT02481674), a completed Phase 2 trial, provided clinical rationale for the ongoing Phase 1/2 SIGNAL‐AD study (NCT04381468).

Method

The SIGNAL‐HD study included 301 subjects with late prodromal (LP) and early manifest (EM) HD. Subjects were treated with monthly infusions of pepinemab for at least 18 months and evaluated for safety and a variety of clinical parameters including cognition (HD‐CAB). Imaging endpoints included structural MRI to assess brain atrophy and FDG‐PET to assess brain metabolism. The SIGNAL‐AD study plans to include 40 subjects with early AD treated for approximately 1 year, with objectives including safety, change in brain metabolism via FDG‐PET, and clinical endpoints including cognition.

Result

In SIGNAL‐HD, pepinemab was well‐tolerated and was shown to cross the BBB to engage its target. Co‐primary efficacy outcome measures did not achieve statistical significance in this study, however, positive trends in the direction of pepinemab benefit were observed and analysis of secondary and exploratory endpoints was therefore pursued. In 179 EM subjects, a treatment benefit was observed in 6/6 components of the HD‐CAB cognitive assessment battery, with a significant treatment effect on HD‐CAB composite score (p = 0.007). Further changes in prespecified exploratory imaging endpoints suggest that pepinemab treatment reduced brain atrophy (volumetric MRI) and slowed or reversed decline in metabolic activity in 26/26 brain regions, with 15/26 regions showing a significant positive treatment effect (p≤0.05) by FDG‐PET imaging.

Conclusion

SIGNAL‐HD showed a favorable safety profile and positive trends in cognition and imaging endpoints that encourage continued development in both HD and AD. The Phase 1b/2a study in AD (SIGNAL‐AD), is currently enrolling and initial safety review is planned for end of February.
Understanding differences in antidepressant use patterns among african american and white volunteers with dementia
Authors: Leoutsakos Jeannie‐Marie S , Rebok George , Thorpe Roland J. , Xue Qian‐Li
Published: June 2023

Background

Older African Americans are less likely to use antidepressants than Older White Americans. These findings are based on cross‐sectional studies or studies with limited followup periods; less is known about patterns of use (initiation, augmentation, switching, discontinuation) over many years. We describe antidepressant use patterns over 5 or more years in a large prospective sample of US volunteers with dementia.

Method

Our sample was 12,627 white and 1,617 African American volunteers (mean: 75.2; SD 10.5) followed approximately yearly at Alzheimer Disease Research Centers 2005‐2020. We used Webplots to visualize antidepressant use patterns over time, and will explore predictors of these patterns.

Result

At their first visit, 413 (21.6%) of African Americans and 5,634 (36.0%) of White Americans were using antidepressants. Among African Americans, 78 (9.3%), 33 (6.6%), and 11 (3.5%) initiated antidepressant use at visits 2,3, and 4, respectively; among White Americans 807 (13.4%), 409 (10.9%), and 211 (9.2%). Among African Americans using antidepressants, 38 (23%), 49 (9.8%), and 30 (9.4%) discontinued antidepressant use at visits 2,3, and 4 respectively; whereas among White Americans, 683 (18.7%), 419 (16.3%), and 302 (16.9%). Among African Americans using antidepressants, 37 (14.5%), 20 (12.5%), and 8 (9.1%) changed their regimen at visits 2,3, and 4 respectively; whereas among White Americans, 526 (14.4%), 239 (10.9%), and 135 (9.7%).

Conclusion

Compared to white volunteers, African American voluntee had lower rates of antidepressant use at baseline and lower rates of initiation at subsequent visits. Rates of discontinuation were higher among African Americans at study visit 2, but lower at later visits. Rates of regimen change were similar by race. Differences in patterns of medication use over time speak to potential equity issues that cannot be observed with cross‐sectional study designs. Further, in order to understand whether these medications are helpful in participants with dementia, it is first important to understand differences in who uses these medications, and which factors predict regimen changes and discontinuation.
Multi‐faceted frail older adults and chronic diseases
Authors: Lee Jiyeon , Park Ji‐Hyuk
Published: June 2023

Background

The older adults who are in the middle of health and disability are called frail older adults because they are vulnerable to disability. Although the relationship between chronic diseases and frailty has been reported through a number of previous studies, the latest studies examining the prevalence of frailty based on multifaceted factors are limited.

Method

In this study, data from the 5th Survey of Living Conditions of Older adults study conducted in 2020 was selected. Data of the older adults over 65 (N = 10,097) were used for the analyses. Using the Comprehensive Korean Frailty Instrument (CKFI), participants were classified into robust, pre‐frail, and frail groups. Binominal logistic regression was used. Analysis was performed using SPSS 25. Three models were set. In Model 1, cutoff was set to 7 points to examine the possibility of chronic diseases in the frail group compared to the robust and pre‐frail groups. In Model 2, cutoff was set to 5 to examine the possibility of chronic diseases in the pre‐frail and frail groups compared to the robust group. In Model 3, except for the frail group, the possibility that the pre‐frail group has chronic diseases compared to the robust group was examined.

Result

The prevalence of robust, pre‐frail and frail group was found to be 26.59%, 27.65%, 45.76% respectively (Table 1). For all models, the probability according to the Likelihood Ratio statistic value was less than 0.01. The p‐value was less than 0.01.

According to z‐statistics of Model 1, it was confirmed that Rheumatoid Arthritis/Osteoarthritis (16.17), hypertension (13.54), diabetes (13.14), lumbago (11.75), stroke (11.96) and osteoporosis (OST) (10.92) affect frailty (Table 2). The z‐statistics of Model 2 confirmed that RHE (12.45), DIA (10.82), high blood pressure (10.62), and LUM (10.15) had the effect of pre‐frail and frail groups (Table 3). In Model 3, there were no results with z‐statistics more than 10. Though the model was significant, the explanatory power was low (Table 4).

Conclusion

We found that there was a significant correlation between multifaceted frailty and chronic diseases. In the future, it is necessary to examine the causal relationship between multifaceted frailty and chronic diseases through longitudinal studies.
Cognitive impairment and depressive symptoms in severe COVID‐19 elderly survivors: Preliminary results from 1‐year follow‐up assessment
Authors: Ribeiro José Pedro , Martins Sónia , Ferreira Ana Rita , Fontes Liliana , Fernandes Joana , Vieira Tatiana , Reis Nuno P , Braga António P , Coimbra Isabel , Paiva José Artur , Fernandes Lia
Published: June 2023

Background

Studies have pointed towards the presence of neuropsychiatric sequelae after COVID‐19 infection, yet in the midst of the biggest health threat of this generation there are relatively few long‐term studies which have endeavored to identify such complications, known to have a negative impact on quality of life. In this context, this study aims to identify cognitive impairment (CI) and depressive symptoms in severe COVID‐19 elderly survivors, 1‐year after hospital discharge and also to analyse the association between CI and depressive symptoms.

Method

This study is part of the longitudinal MAPA project still ongoing at a University Hospital in Porto, Portugal. Patients with >60 y.o., admitted into Intensive Care Medicine Department (ICMD), due to COVID‐19 (1st wave), were included. Exclusion criteria were: ICMD length of stay ≤24h, terminal illness, major auditory loss or inability to communicate at the follow‐up assessment. Participants were evaluated 1‐year after hospital discharge, with a research protocol, which includes Patient Health Questionnaire (PHQ‐9; depressive symptoms) and Six Item Cognitive Impairment Test (6CIT; CI).

Result

Thirty‐eight patients were included (median age = 71years). Mostly were male (66%), married (66%) and with low education (58% = 0‐4years). About 53% had previous psychiatric history (none had clinical registry of CI or dementia). Most patients (71%) needed deep sedation and invasive mechanical ventilation (71%). CI and depressive symptoms were observed in 18.4% of the sample, for both. Patients with depression had more CI (42.9%vs12.9%), however this difference was not statistically significant.

Conclusion

These findings showed that an important proportion of severe COVID‐19 elderly survivors suffers from depressive symptoms and CI, 1‐year post‐discharge, which are in line with other studies. These results underline the need to better clarify the long‐term relationship between depression and CI in severe COVID‐19 survivors.
Cognitive impairment and COVID‐19 in an urban indigenous community from Amazonas
Authors: Bezerra Camila Carlos , Toledo Noeli N , Duarte Vanessa Vasconcellos , Sampaio Rebeca Lima , Brucki Sonia Maria Dozzi , Souza‐Talarico Juliana Nery
Published: June 2023

Background

Like all minority groups worldwide, indigenous populations were most impacted by the COVID‐19 pandemic, especially in low‐middle income countries (LMICs). However, little is known about the relationship between previous COVID‐19 and cognitive performance. This study aimed to identify the prevalence of cognitive impairment and its relationship with previous COVID‐19 in indigenous mid‐aged and older adults.

Methods

Using a cross‐section approach, 134 indigenous people, 50 years and older, from an urban dwelling community located in Manaus, Amazonas, Brazil, were evaluated for cognitive impairment and previous covid‐19 disease. Cognitive impairment (CI) was based on consensus diagnostic guided by the following criteria: 1) scores on Mini‐Mental State Examination (MMSE) ≤ 14 for illiterate subjects and ≤ 19 for literate subjects (mean minus two standard deviations); 2) scores ≤ 8 on verbal fluency or ≤ 7 on delayed recall on the Brief Battery for Cognitive Screening. All those tests and criteria were already used in Brazil’s previously indigenous community and population with a low‐education level.

Results

30.6% of the urban indigenous community met the criteria for cognitive impairment, among them 48.8% tested positive for COVID‐19 since the pandemic has started. Logistic regression show that low education increases the changes of cognitive impairment (OD = 0.839; 95% CI = 0.748 – 0.942; p = 0.003) while previous COVID‐19 did not (OD = 0.495; 95% CI = 0.224 – 1.094; p = 0.082).

Conclusion

The prevalence of cognitive impairment in an urban community of Brazilian indigenous people increased in older adults with lower education levels regardless of previous COVID‐19.
Magnetoencephalography(MEG) spectral signature of cognitive impairment ‐ A perspective on pathophysiological changes with blood pressure
Authors: Srivastava Pallavi , Proskovec Amy L , Rossetti Heidi , Yu Fang F. , Berry Jarett D , Maldjian Joseph , Davenport Elizabeth M
Published: June 2023

Background

Spectral ratios (e.g., resting‐state EEG alpha/theta power ratio), which index rhythmic brain activity, have been shown to distinguish early‐onset AD from healthy controls. Magnetoencephalographic (MEG) brain imaging offers advantages over EEG through its unique combination of excellent temporal as well as spatial precision for detecting brain activity. The purpose of this study is to compare MEG spectral activity in cognitively impaired and healthy controls with changes in systolic blood pressure (sbp), specifically focused in the frontal lobe as this region is known to be susceptible to hypertension related white matter degradation.

Methods

Sixteen cognitively impaired, including 13 possible and 3 probable mild cognitive impairment (MCI), (mean age 65.6 years, males/females: 5/11, Whites/Blacks: 11/5) and sixteen age, sex, and race matched healthy controls (mean age 62.4 years, males/females: 4/12, Whites/Blacks: 11/5) were recruited from an ongoing multiethnic community‐based study to complete six minutes of resting‐state MEG along with a T1w brain MRI. All MEG data underwent standard preprocessing. Resultant whole‐brain maps of spectral activity were filtered into six canonical frequency bands, including delta (2‐4 Hz), theta (5‐7 Hz), alpha (8‐12 Hz), beta (15‐29 Hz), gamma (30‐59 Hz) and high gamma (60‐90 Hz). Relative mean power of each frequency band, and spectral ratios of alpha/theta, beta/delta as well as a spectral slowing index [(alpha+beta+gamma)/(delta+theta)] were computed.

Result

Mean sbp was 135 mm Hg for both groups. Generalized linear regression models showed cognitive impairment was negatively associated with spectral ratios beta/delta and spectral slowing index. We also found a significant positive association between spectral ratios (beta/delta β = ‐0.0115, p = 0.0015; spectral slowing index β = ‐0.0125, p = 0.0144) and interaction of systolic blood pressure with cognitive impairment. Results are summarized in tables 1‐2.

Conclusion

Lower spectral ratios have previously been demonstrated in individuals with AD. Somewhat surprisingly, our findings indicate that lower blood pressure is associated with lower values on these MEG metrics in cognitively impaired individuals. Interestingly, overtreatment of hypertension in elderly with MCI has been associated with greater cognitive decline. Thus, these results will be examined in a larger cohort and the analysis will be expanded to include anti‐hypertensive medication data to potentially explain the above findings.
Analysis of epigenetic mediators for the effect of Polyunsaturated fatty acids Omega6/3 ratio on cognitive function and progression to dementia
Authors: Andrade Victor
Published: June 2023

Background

Previous research reported the association between circulating Omega‐3 polyunsaturated fatty acids (PUFA) in blood and the risk of dementia and Alzheimer’s disease (AD). However, a large intervention study supplementing Omega‐3 reported that this supplementation has only a marginal effect on improvement of cognitive performance after the supplementation. Since PUFA metabolism shared the processing enzymes, we explored whether the relationship between two main families of PUFA, i.e., Omega‐3 and Omega‐6, might associate with cognitive performance. Hence, we observed that the ratio Omega‐6/Omega‐3 in blood is associated with cognitive decline and dementia. To follow up on this finding, we sought to explore whether modulation of immune response and inflammation may underlie these effects.

Method

Three independent cohort were used for this study: i) the observational memory‐clinic‐based cohort DELCODE (n = 1036); ii) the primary care‐derived cohort AgeCoDe (n = 1252); iii) the Multidomain Alzheimer Preventive Trial (MAPT study) cohort (n = 1679). Omega‐3 and PUFA levels were quantified specifically in plasma from each cohort. COX regressions and linear mixed models were applied to evaluate PUFA ratio effect on cognitive performance and progression to dementia. Genomic and epigenomic modulators for the observed effects were further explored using the previously published tool (MetaMeth). Results were confirmed using our pipeline for epigenome‐wide association study (EWAS).

Result

Omega‐6/Omega‐3 ratio is associated with cognitive performance and risk of progressing to AD in DELCODE and AgeCoDe. In MAPT, the improvement of this ratio is associated with improvement on cognitive performance. Moreover, levels of Omega‐3 in blood modulate methylation of genes coding for key enzymes of PUFA metabolism. Our data showed that the biological effect for some genetic susceptibility signals for AD is mediated by changes in DNA methylation, including immune‐related genes like MS4A and TREM2.

Conclusion

Our data suggests that balance between PUFA is relevant on cognitive decline and dementia. In addition, the genetic effect of risk variants located at the AD risk loci containing the MS4A gene cluster and TREM2 are mediated by changes in methylation. To provide a connection between PUFA and neuroinflammation in the context of AD, we are currently exploring the effect of PUFA levels on DNA methylation at MS4A and TREM2 loci.
A study protocol on teaching english to people with mild cognitive impairment with the use of songs
Authors: Makri Marina , Christakidou Alexandra , Tsolaki Magda
Published: June 2023

Background

People with Mild Cognitive Impairment (MCI) need to improve their cognitive functions in order to avoid the deterioration of their condition. Cognitive abilities can be improved by learning a foreign language. Due to the cognitive deficits of MCI people, conventional methods that teaching English cannot have significant results. The use of songs in teaching English is proved to be a promising method for more effective acquisition of the language while also improving cognitive functions and symptoms of depression and anxiety.

Method

This learning method had been designed by combining elements from four methodologies in language learning “Communicative Language Teaching”, “Natural Approach”, “(De) suggestopedia” and “Neurolinguistic Programming (NLP)”. The intervention of this study involves a randomized controlled trial design with two arms (an intervention arm and a control group) over a nine‐month period and will be provided twice a week. Participants will be people with MCI aged 60‐85 years, of both genders. A sample size of 90 participants is targeted based on expected neuropsychological test performance, and drop‐out rates. Interventions will be provided by trained staff with a control group not receiving any intervention but continuing life as usual. Assessments will be done at baseline, and nine months, and include neuropsychological tests to measure for changes in cognition. Secondary outcome measures will include mood changes in anxiety, depression and quality of life. All efficacy statistical analysis will be carried out on an intention to treat basis. Primary and secondary outcomes will be modeled using the linear mixed model for repeated measurements and further analysis will be undertaken.

Result

This study protocol is implementing by Greek Association of ALzheimer Disease and Related Disorders and the final results will be announced soon.

Conclusion

This will be the first study to implement and assess this intervention in a randomized controlled trial. We expect that this study protocol could prevent cognitive decline, decrease symptoms of depression and anxiety and significantly impact quality of life and the wellbeing of people with MCI.
Ethics and the predictive turn in Alzheimer’s
Authors: Stümpel Johanne , Snijders Katharina Elisabeth , Boada Mercè , Frisoni Giovanni B , Marquié Marta , Ribaldi Federica , Rostamzadeh Ayda , Schmitz‐Luhn Björn , Schwegler Carolin , Jessen Frank , Woopen Christiane
Published: June 2023

Background

Rising knowledge about fundamental molecular mechanisms of diseases, the possibility to digitally collect a wealth of lifestyle data, and increasing diagnostic capabilities in early risk prediction make it as easy as never before to calculate a personalized risk for future diseases. Knowing and influencing that risk becomes a matter of personal choice and responsibility. Consequences both on the individual and on the societal level result from this predictive turn in medicine. By means of the evolving accessibility and reliability of biomarker‐based diagnostics and risk prediction in Alzheimer’s disease (AD), we address the ethical perspective on this highly relevant topic.

Method

In the ethical part of the PreTAD project, we pursue a Mixed‐Methods approach and will (1) conduct a survey with 150 individuals within the healthy population (50 per participating country; baseline + 6‐month follow‐up). Participants will be surveyed with quantitative standardized tests, newly developed questions, and by utilizing hypothetical scenarios of AD biomarker risk disclosure. Employing hypothetical scenarios serves to reveal the needs and attitudes of healthy individuals regarding early prediction of AD. We will (2) conduct 40 narrative interviews (baseline + 6‐month follow‐up) with healthy individuals, healthy individuals at risk (AD family history or APOE4 carriers), individuals diagnosed with subjective cognitive decline (SCD) (> 4 weeks), and individuals with recent (≤ 4 weeks) SCD diagnosis.

Result

Predictive knowledge can be associated with different perspectives on the self, discrimination and (self‐)stigmatization. We therefore address self‐perception, self‐determination as well as identity and authenticity with regard to the attitudes of people sharing different prior experiences with AD. We want to learn about the relationship between identity, authenticity and attitudes toward a personalized risk profile for future disease. Additionally, we aim at highlighting the individual’s needs in the course of an AD risk prediction in different groups of individuals, providing a detailed analysis of this phenomenon in a trinational and interdisciplinary (clinical, ethical, legal and linguistic) perspective.

Conclusion

In this presentation, we will outline the methodology of a multilevel ethical analysis on fundamental questions of the paradigm shift towards predictive medicine ‐ exemplified by AD.
The association between electrophysiological and neuropsychological measures and cardiovascular disease in patients with Alzheimer’s Disease dementia
Authors: Marin Anna , Schiloski Kylie A , DeCaro Renee , Vives‐Rodriguez Ana , Budson Andrew E , Turk Katherine W
Published: June 2023

Background

Electrophysiological and neuropsychological measures are useful markers of Alzheimer’s Disease (AD); however, it is still unclear how these measures relate to the cardiovascular profile of AD patients, and their influence on disease progression and management. Our study examined how electrophysiological and neuropsychological measures are associated with cardiovascular risk factors and the severity of small vessel disease among patients with AD dementia.

Method

Data were collected using a seven‐electrode COGNISION™ rig in 185 older veterans from the VA Boston Healthcare system memory disorders clinic. EEG/ERP data were recorded while participants completed a three‐tone auditory oddball task. All subjects were administered a neuropsychological battery composed of 8 subtests. Through review of medical history, we selected a subset of patients (N = 46) that met the following criteria: core clinical criteria for probable AD dementia, ≥ 65 years of age, and MMSE score between 20 and 26. We categorized these patients based on their number of cardiovascular risk factors—among hypertension, type 2 diabetes or prediabetes, hypercholesterolemia, and body mass index (BMI) ≥ 25 kg/m2 —and their small vessel disease severity (absent, mild, moderate, or severe). Spearman correlations were computed to assess the association of electrophysiological and neuropsychological measures with the number of cardiovascular risk factors and the severity of small vessel disease.

Result

Alpha peak frequency was positively correlated with the number of cardiovascular risk factors (p = .011) and was inversely correlated with small vessel disease severity (p = .029). N100 standard latency was inversely correlated with small vessel disease severity (p = .018). Scores on the verbal phonemic fluency test were inversely correlated with the number of cardiovascular risk factors (p = .014), while scores on the verbal category fluency test were inversely correlated with small vessel disease severity (p = .023).

Conclusion

Alpha peak frequency, N100, and verbal fluency scores are associated with the number of cardiovascular risk factors and small vessel disease severity in AD patients. Overall, these electrophysiological and neuropsychological measures represent a clinical tool to help characterize the cardiovascular profile of patients with AD dementia, and its contribution to overall disease progression.
A longitudinal study of the task‐related activation trajectory in people with mild cognitive impairment and subjective cognitive decline
Authors: Correa‐Jaraba Kenia Shaily , Mellah Samira , Dialahy Isaora Zefania , Group CIMA‐Q , Belleville Sylvie
Published: June 2023

Background

Brain hyperactivation — defined as higher level of activation compared to controls — was suggested as a very early signature of prodromal Alzheimer’s disease (AD), which would gradually decrease with progression to dementia. Longitudinal studies with people who have mild cognitive impairment (MCI) and subjective cognitive decline (SCD) can be used to capture the temporal dynamics and inter‐individual differences of these very early activation changes. Here, we aimed to identify the temporal trajectory of task‐related activation in participants with SCD and MCI from the CIMA‐Q cohort, which has data collected at multiple time‐points. We thus identified subgroups based on their common activation trajectory and characterized subgroups defined from the activation trajectory.

Method

The study included 53 older participants (40 SCD; 13 MCI) from the CIMA‐Q cohort with neuroimaging data collected over at least two time‐points (66‐85 years old; 36 women, 17 men). An fMRI examination was done every two years (2‐4 time‐points; average follow‐up: 3.2 years). Task‐related activation was measured during an associative memory encoding task. Group‐based trajectory models were estimated to identify homogeneous groups of participants based on activation trajectories in the hippocampus and in regions from the cortical signature of AD. Groups defined based on activation trajectories were then compared using Apolipoprotein‐ε4 (ApoE4), baseline cognition and hippocampal volume.

Result

Two different trajectories of activation were identified: Trajectory 1 was found in several cortical regions and was characterized by a high level of initial activation, which decreased over time. Trajectory 2 was characterized by a lower activation level, which remained stable over time or increased slightly on time‐point 4. Smaller hippocampal volume and ApoE4 were associated with Trajectory 1 for the left angular gyrus, and left hippocampal and right middle temporal gyrus activation, respectively.

Conclusion

An inverted U‐shape trajectory was found with high activation followed by gradually decreasing activation in AD‐signature regions. This trajectory was associated with smaller hippocampal volume and/or the presence of ApoE4 allele, both of which are biomarkers that increase the likelihood of developing AD. This finding supports the hypothesis that the inverted U‐shape trajectory of hyperactivation could be an index of prodromal AD.
Transcription‐based drug repurposing in Alzheimer disease psychosis
Authors: Kouhsar Morteza P , Creese Byron , Weymouth Luke Stephen , Smith Adam R. , Bergh Sverre , Wedatilake Yehani , Selbæk Geir , Torkamani Ali , Mill Jonathan , Ballard Clive G , Sweet Robert , Kofler Julia , Pishva Ehsan , Lunnon Katie
Published: June 2023

Background

There are at least 50 million people with Alzheimer’s Disease (AD) or other dementias worldwide. About 50% of people with AD may develop psychotic symptoms (delusions and hallucinations). However, there is no effective pharmacological therapy for psychosis in AD and all current treatments are based on antipsychotics originally designed for other disorders like schizophrenia. In this study, we identify the molecular signature of psychosis in AD in post‐mortem brain samples and then use the connectivity map (CMAP) and library of network‐based cellular signatures (LINC) to predict candidate drugs based on the disease transcriptional signature.

Method

We generated RNA‐Seq data (Illumina Stranded mRNA Prep) and compared the gene expression levels across 4 groups: Control, AD with no psychosis (AD), AD with Delusions (ADD), and AD with both Delusions and Hallucinations (ADDH). The final identified differentially expressed up and down‐regulated genes (DEGs) were used as query signatures in the CMAP and LINC databases to identify drugs that could potentially reverse the gene expression signatures in disease samples. To investigate the disease mechanisms and the effect of repurposed drugs on it, a drug‐target interaction network was reconstructed and combined with the human interactome. Enrichment analysis of this network identifies AD and psychosis‐related pathways and the potential effect the nominated drugs have on them.

Result

After filtering out the common DEGs, 357, 171, and 66 unique genes remained in the AD, ADD, and ADDH signature sets, respectively. The signatureSearch package was used to search transcriptome signatures against CMAP and LINC. The top ranked drugs, based on negative connectivity scores, were selected as final results. Gene set enrichment analysis of the drug target genes presented some key pathways and activities related to psychiatric disorders. For example, serotonin receptor signalling pathway is one of the most over‐represented pathway of target genes in both ADD and ADDH groups.

Conclusion

This study can improve our understanding of the molecular mechanisms underlying AD psychosis. The candidate drugs we have identified could be repurposed for clinical trials of psychosis in AD and provide valuable knowledge for future pharmacological research.
High CSF cortisol levels are associated with frontal lobe and hippocampal atrophy across patients on the Alzheimer’s disease spectrum
Authors: Souza Laura Willers , Bieger Andrei , Borelli Wyllians Vendramini , De Bastiani Marco Antônio , Negrini Guilherme Bauer , DuBois Jonathan M , Zimmer Eduardo R. , Lab Zimmer Neuroimaging
Published: June 2023

Background

Multiple studies have linked high cerebrospinal fluid (CSF) cortisol levels, a frequently used biomarker of stress, with the Alzheimer’s disease (AD) pathophysiology. However, the relationship between CSF cortisol levels and AD‐related brain atrophy is not fully understood. Thus, this study sought to determine the association between CSF cortisol levels and neuroimaging biomarkers of brain structure indexed by magnetic resonance imaging (MRI) in patients across the AD spectrum.

Methods

Participants with baseline measures of CSF cortisol and structural (high‐resolution T1‐weighted) MRI (n = 300) were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The MRI scans were processed with FreeSurfer (v. 7.1.1), and the statistical analyses were performed using R (v. 4.1.1; R Core Team, 2021). We performed a region‐of‐interest (ROI) analysis using a generalized linear model (GLM), to assess the association between CSF cortisol levels and (1) volume of hippocampus, amygdala, subcortical and cortical segmentation, (2) cortical thickness and (3) surface area of cortical structures (Fig. 1). The ROI analysis was corrected by Bonferroni (p < 0.0005).

Results

CSF cortisol levels did not correlate with left hippocampal volume (p = 0.2; Fig. 2A) and mean global brain thickness (p = 0.002; Fig. 2C). However, we found a negative correlation with the volume of left fimbria (r = ‐0.20, p = 0.0003; Fig. 2B) and right superior frontal thickness (r = ‐0.21, p = 0.0003; Fig. 2D). In the regression model, only right superior frontal thickness showed significant association with CSF cortisol levels after adjusting for age (corrected R2 = 0.11, p < 0.0001). The other regions and parameters analyzed did not present significant correlations with CSF cortisol levels.

Conclusions

This cross‐sectional study found an association between elevated CSF cortisol levels and atrophy of left fimbria and right superior frontal in patients on the AD spectrum. Our findings suggest a particular vulnerability to cortisol in selected regions. To the best of our knowledge, this is the first study to assess the associations between CSF cortisol levels and ROIs from hippocampus and amygdala segmentation. Our results have potential implications for understating AD‐related brain atrophy and developing innovative therapeutic strategies.
Are there measurement invariance in subjective cognitive decline instruments across diverse ethnoracial groups?
Authors: Lee Athene KW , De Vito Alyssa N. , Brick Leslie Ann D , Coutinho Maria Teresa , Correia Stephen
Published: June 2023

Background

Subjective cognitive decline (SCD) indicates a likelihood of the presence of cerebral beta‐amyloid burden associated with preclinical Alzheimer’s disease (AD), future objective cognitive decline, and clinical progression to dementia. The applicability of SCD as a preclinical AD marker in diverse ethnoracial groups has not been validated. In the few studies with diverse samples, participants from under‐represented populations such as Latinx and Black, tend to endorse differing levels of SCD than Non‐Hispanic White (NHW) individuals. Better understanding of ethnoracial differences in SCD and addressing potential cultural biases in existing measures are critical to validate its use as a preclinical AD marker in diverse samples. In this study, we examined two SCD instruments to evaluate measurement invariance across ethnoracial groups.

Method

807 participants aged ≥55 who reside in the United States (298 Latinx, 270 Black, 239 NHW) were recruited through Amazon’s Mechanical Turk and Qualtrics Panel. We examined the psychometric properties of the Cognitive Change Index (CCI) and Cognitive Function Index (CFI) across ethnoracial groups. First, we evaluated the factor structure of each measure using split‐half exploratory and confirmatory factor analyses (EFA/CFA). Next, we used multiple‐group CFA to evaluate configural, metric, and scalar invariance via a step‐wise approach.

Results

Participants (mean age of 65), were mostly women (63%) and received education beyond high school (83%). Split‐half EFA/CFA on the whole sample supported a one‐factor solution for both measures. Multiple‐group CFA revealed that when race/ethnicity was considered, model fit was negatively impacted. Neither measure achieved metric invariance, indicating that factor loadings were not equivalent across groups. For example, the CFI item “memory has declined substantially” had the highest loading for NHW and Latinx, but was low for the Black group. Conversely, “trouble following the news” loaded high for Latinx and Black, but low for NHW.

Conclusion

Measurement invariance was not supported for either instrument, indicating that it cannot be assumed that the same construct is being measured across NHW, Latinx and Black individuals. Scale refinement, such as abbreviating SCD measures to include only items that perform well across all groups, may minimize biases and facilitate cross‐cultural comparison in preclinical AD research.
Physical activity engagement, memory function, and hippocampal volume in adults with down syndrome
Authors: Peven Jamie C , Handen Benjamin L. , Laymon Charles M , Fleming Victoria L , Piro‐Gambetti Brianna , Christian Bradley T. , Klunk William E , Cohen Ann D. , Hartley Sigan L
Published: June 2023

Background

Higher engagement in moderate‐to‐vigorous physical activity (PA) is related to better cognitive functioning in neurotypical adults; however, little is known about the impact of PA on cognitive aging in adults with Down syndrome (DS). Individuals with DS have three copies of the chromosome 21, which includes the gene for the amyloid precursor protein, resulting in an increased risk for/earlier onset of Alzheimer’s disease. The goal of this study was to understand the relationship between moderate PA engagement and memory functioning in non‐demented adults with DS.

Method

Adults with DS participated in an ancillary Lifestyle study linked to the Alzheimer’s Biomarkers Consortium for Down Syndrome (N = 54). Participants completed the Cued Recall Test (CRT) to measure episodic memory. The total free + cued CRT score was used in analyses. Participants wore a wrist‐worn accelerometer (GT9X) for 7 days to measure PA. Moderate PA was classified using the Freedson cutpoints in ActiLife software and was defined as the daily average minutes. Structural MRI data were acquired within 18 months of actigraphy/cognitive data collection. Hippocampal volume was extracted using Freesurfer v5.3. Associations between moderate PA engagement, memory, and hippocampal volume were evaluated with hierarchical linear regressions controlling for relevant covariates (age, body mass index (BMI), intracranial volume (ICV)).

Result

Participants were 37.81 years old (SD = 8.15 years) and 55.6% female. They spent ∼10.67% of their time engaged in moderate PA (SD = 7.48%). Participants recalled an average of 32.09 items on the CRT (SD = 6.09, range = 7‐36). After controlling for age and BMI, greater moderate PA engagement was associated with higher total recall score (b = 0.279, p = 0.044). After controlling for age and ICV, moderate PA engagement was not significantly associated with hippocampal volume (p = 0.48). Greater hippocampal volume was associated with higher total recall score after controlling for age and ICV (b = 0.496, p = 0.004).

Conclusion

A higher proportion of time spent engaging in moderate PA was related to better memory function in adults with DS. While greater hippocampal volume was related to better memory performance, it was not associated with moderate PA engagement. Greater moderate PA engagement may be a promising lifestyle behavior to preserve memory in aging adults with DS.
Federated Deep Learning for Detecting Alzheimer’s Disease in Multi‐Cohort Brain MRI
Authors: Stripelis Dimitris , Dhinagar Nikhil J , Romero Rafael V. Sanchez , Thomopoulos Sophia I , Thompson Paul M , Ambite Jose Luis
Published: June 2023

Background

Deep learning shows promise in detecting Alzheimer’s Disease (AD) based on brain MRI1. Models trained on limited samples may fail when applied to new datasets (other cohorts, scanners), but privacy concerns make it difficult to centralize large amounts of data2. To address this, we developed a general federated learning architecture3, which we applied to train a 3D convolutional neural network (CNN) to detect AD from T1‐weighted brain MRI data from the three independently collected phases of the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Method

We trained a 3D‐CNN over a federated learning environment of 3 sites corresponding to each ADNI phases (ADNI1, ADNI2/GO, ADNI3). No subject data are shared across sites, only model parameters, thus satisfying privacy/regulatory requirements. Each site trains the model on its own local dataset for several epochs and shares only the locally‐trained parameters with a central server. The server aggregates the parameters and computes the global model, which is sent back to each learner, and the process repeats.

We trained each learner for 4 local epochs in between federation rounds for a total number of 25 rounds. We divided each ADNI dataset into training, validation and test sets with distribution 70/20/10% (Figure 1). We also compared the performance of training our CNN models with random initialization versus using pre‐trained weights from a UK Biobank MRI sex classification task.

Result

Table 2 shows the accuracy, precision, recall and F1 scores for our federated CNN, compared to a centralized model that was trained over all ADNI data. All models achieved excellent performance for classifying AD (96‐98%). Overall, the federated model with pretrained weights performed best. Pre‐training boosted accuracy for the federated, but not the centralized, case.

Conclusion

Federated learning achieves high performance in AD prediction from MRI and promises new applications in neuroimaging.

[1] Lu et al. A Practical Alzheimer Disease Classifier via Brain Imaging‐Based Deep Learning on 85,721 Samples. bioRxiv 2020_08_18_256594. 2021

[2] Ming et al. COINSTAC: Decentralizing the future of brain imaging analysis. F1000Research 6:1512, 2017.

[3] Stripelis et al. Scaling Neuroscience Research using Federated Learning. ISBI 2021.
Feasibility of frequent self‐administered mobile cognitive assessments in adults with and without cognitive impairment
Authors: Christianson Kieffer , Prabhu Meha , Popp Zachary T , Rahman Md Salman , Drane James , Lee Marissa , Lathan Corinna , Lin Honghuang , Au Rhoda , Sunderaraman Preeti , Hwang Phillip H
Published: June 2023

Background

Traditional paper and pencil approaches measure cognitive performance at one time point. Early indications of cognitive impairment often appear irregularly, suggesting diagnoses derived from a single session can fail to characterize normal fluctuations and lead to inaccurate conclusions. Mobile applications enable brief cognitive assessments to be completed frequently and remotely. However, the feasibility of older adults adhering to a schedule of repeated self‐administered cognitive assessments is unclear. We tested the repeated use of a mobile assessment among older adults as a potential method for collecting cognitive performance data to detect early signs of cognitive impairment.

Method

The current study included 33 participants (n = 23 cognitively unimpaired, n = 10 cognitively impaired) recruited from the Boston University Alzheimer’s Disease Center. A remote practice session using the Digital Automated Neurobehavioral Assessment (DANA) mobile application was completed prior to beginning an assessment schedule consisting of three assessments within the first week (segment 1) and one assessment per week during the following three weeks (segment 2). Feasibility was measured via schedule adherence across segments, stratified by age and cognitive status. Cognitive efficiency, a derived measure of speed and accuracy, was compared for the Procedural Reaction Time (PRT) task at the first assessment and longitudinally across segments 1 and 2. Demographics including age, sex, race, education, and mobile device type were also collected (Table 1).

Result

Across all segments, 90.9% of participants adhered to the assessment schedule with a ±1 day grace period applied. Adherence was similar between each segment, and by cognitive status and age group (Table 2). No significant differences in cognitive efficiency were observed on the PRT task between cognitive groups (Figures 1‐2, Table 3).

Conclusion

Our findings suggest that older adults, including those with cognitive impairment, are capable of completing self‐administered remote smartphone assessments at a high‐frequency. Traditional analytic methods failed to differentiate cognitive groups based on mean cognitive performance; however, between‐group comparisons could mask within‐person fluctuations characteristic of cognitive impairment. Therefore, further study with a longer longitudinal assessment period and larger sample size will be required to determine whether more advanced analyses can distinguish impairment status based on cognitive performance patterns.
Distinct regional and hemispheric tau distributions in Primary Progressive Aphasia with neuropathologic Progressive Supranuclear Palsy: A stereological study
Authors: Zouridakis Antonia , Kawles Allegra , Minogue Grace , Keszycki Rachel M , Coventry Christina , Weintraub Sandra , Rogalski Emily J , Flanagan Margaret E , Mao Qinwen , Bigio Eileen H , Mesulam M.‐Marsel , Geula Changiz , Gefen Tamar
Published: June 2023

Background

Primary Progressive Aphasia (PPA) is a dementia syndrome characterized by isolated and progressive impairment of language and focal atrophy of left‐hemispheric cortical regions. PPA presents with various underlying FTLD‐tauopathies such as Pick’s disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). This study investigated clinicopathologic concordance between the aphasic phenotype of PPA and regional distributions of PSP markers quantified in language‐related cortical areas and the dentate gyrus (DG) of the hippocampus—an area of interest due to intact memory exhibited in PPA. Another goal was to compare regional distributions of tau‐positive markers in PSP compared to CBD and PiD to identify differential susceptibility patterns across FTLD‐tauopathies.

Method

Paraffin‐embedded sections were stained immunohistochemically with AT‐8 to visualize neuronal tau inclusions and astrocytes containing phosphorylated tau in 8 right‐handed cases with PPA and autopsy‐confirmed PSP. Modified unbiased stereology was performed in bilateral middle frontal gyrus (MFG) and inferior parietal lobule (IPL), and left DG. A secondary analysis compared distributions of tau markers in cases with PiD (N = 6; tau‐positive inclusions) and CBD (N = 4; tau‐positive inclusions + astrocytic plaques). One‐way ANOVAs and students’ t‐tests were used to analyze distributions.

Result

Within the PSP group, there was significant left‐sided asymmetric predominance of tau‐positive neuronal inclusions and astrocytic tau in cortical areas; left MFG showed over double the total marker density vs right (3,490 vs 1,549 counts/mm3, respectively; p<0.05). In PSP, there was significantly less tau‐positive inclusions and astrocytes in the DG relative to cortical regions, where the ratio of left‐sided dentate‐to‐cortical inclusions was ∼1:2. This was remarkably lower than dentate‐to‐cortical ratios of ∼2:1 in CBD and ∼3:1 in PiD (p<0.01). Finally, PSP cases showed significantly greater astrocytic tau in cortical regions compared to CBD, by ∼100 fold in the left hemisphere (p<0.01).

Conclusion

Findings from this stereological study of PPA with FTLD‐PSP show leftward cortical predominance of pathology concordant with the salience of the aphasic phenotype. Dentate predominance of pathology in PPA due to FTLD‐tau remains a mystery. The relative distribution of dentate‐to‐cortical tau pathology is different across FTLD‐tau species, offering insights into the selective vulnerability of distinct neuronal populations in neurodegenerative dementias.