bluuebunny/crossref_metadata_2025 huggingface dataset:
The association between cannabis use and neuroimaging measures in older adults: Findings from the UK Biobank
Authors: Vered Shiraz , Sznitman Sharon , Weinstein Galit
Published: January 2025

Background

Cannabis use has increased substantially in recent years, for both recreational and medicinal purposes. While the deleterious effects of cannabis use during adolescence on brain health are well acknowledged, long‐term implications of cannabis use on brains of older adults remain unknown. We explored the associations between past and current cannabis use and volumetric brain MRI measures in older participants of the UK biobank.

Method

This cross‐sectional and longitudinal study (with repeated MRI measures) included dementia‐free UK Biobank participants aged ≥60 years who had data on cannabis use and brain MRI outcomes. Linear regression models were used to assess the relationship of self‐reported cannabis use and patterns of use (i.e., frequency, duration, age of onset) with volumetric brain MRI measures, adjusting for sociodemographic factors and health behaviors. To evaluate change between two MRI examinations, we used the second MRI measures as dependent variables while controlling for the first MRI measures and other covariates.

Result

The sample included 19,932 participants (mean age 68±5 years, 48% men), of which 3,800 (19%) reported lifetime use of cannabis. The cross‐sectional analyses revealed that cannabis users had significantly smaller total brain, white matter, grey matter and cortical grey matter volumes compared to non‐users (b = ‐7110±1181; p<0.001, b = ‐4923±780; p<0.001, b = ‐2031±705; p = 0.004 and b = ‐2334±617; p<0.001, respectively). Stronger associations with brain MRI measures were observed among current vs. former users, and in those who used frequently, started using at younger ages and used for longer time periods (Table 1). In contrast, longitudinal analyses showed that cannabis use may be associated with a slower decline in total brain and cortical grey matter volumes (b = 3315±1582; p = 0.036, 0.22% between‐group difference and b = 2320±910; p = 0.011, 0.38% between‐group difference, respectively) (Figure 1).

Conclusion

Our study suggests that cannabis use and patterns of use during the life‐course may be related to detrimental brain health effects (e.g. smaller grey and white matter volumes) in middle‐age and older adults. On the other hand, our findings further suggest a possible protective effect (e.g. slower decline in brain volumes) of cannabis use among cannabis users compared to non‐users, which needs to be validated in future research.
Plasma and neuroimaging biomarkers of small vessel disease and Alzheimer’s disease in a diverse cohort
Authors: Lockhart Samuel N. , Sutphen Courtney L. , Tanley Jordan E. , Gonzalez‐Ortiz Fernando , Kac Przemyslaw Radoslaw , Habes Mohamad , Heckbert Susan R. , Ashton Nicholas J. , Mielke Michelle M. , Whitlow Christopher T , Hiatt Kevin , Craft Suzanne , Register Thomas C. , Hayden Kathleen M. , Rapp Stephen R. , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Hughes Timothy M.
Published: January 2025

Background

Little is known about how plasma Alzheimer’s disease (AD) biomarkers relate to neuroimaging biomarkers of cerebral small vessel disease (cSVD) in the context of neurodegeneration and AD pathology in late life.

Method

This cross‐sectional study included 251 Multi‐Ethnic Study of Atherosclerosis (MESA) Exam 6 participants with plasma AD biomarkers (Aβ42/Aβ40, GFAP, NfL, p‐tau181, p‐tau217, p‐tau231; Quanterix SIMOA), MRI (neurodegeneration and cSVD), PiB (amyloid) PET, and UDSv3‐based adjudicated cognitive status (69% cognitively normal, 27% MCI, 4% probable dementia) data at the Wake Forest site. Multivariable models examined relationships among cognitive status, plasma, and neuroimaging biomarkers (covariates: age, education, race, gender, smoking status, kidney function [eGFR], APOE‐ε4, BMI; significance at p<.05 uncorrected).

Result

Cognitive status associated with imaging biomarkers and with plasma biomarkers of Aβ42/Aβ40, GFAP, p‐tau217 and p‐tau231. No NfL or p‐tau181 group differences were observed (Table 1). Lower plasma Aβ42/Aβ40 (Table 2) was associated with lower gray matter (GM) volume (GMV) and hippocampal volume (HCV); higher GFAP levels were associated with lower HCV. Higher NfL levels were associated with lower GMV and HCV, and with higher GM Free Water (FW). Higher p‐tau217 levels were associated with lower GMV. Plasma p‐tau231 was not associated with neurodegeneration imaging biomarkers. Higher NfL levels were associated with higher white matter (WM) hyperintensity (WMH) volume and WM FW. All plasma tau measurements were positively associated with WM FW but not other cSVD biomarkers. Lower Aβ42/Aβ40 ratio was significantly associated with greater prevalence of microbleeds. Higher GFAP was associated with higher WMH volume. As anticipated, lower plasma Aβ42/Aβ40 ratio and higher p‐tau217 and p‐tau231 were associated with higher Aβ deposition and odds of Aβ positivity (Table 3); a doubling in the level of p‐tau217 or p‐tau231 was associated with a 2‐3 fold increase in the odds of Aβ PET positivity.

Conclusion

We found that plasma GFAP, NfL, p‐tau181, p‐tau217, and to a lesser extent p‐tau231 are associated with cognitive status, vascular comorbidities and imaging biomarkers of cSVD, in addition to measures of AD‐related pathology. Importantly, we demonstrated novel associations between plasma AD biomarkers of p‐tau and NfL with cSVD measures of WM structural health.
Cyclomatic Complexity: A Novel Approach for Analyzing Movement with Machine Learning to Predict Mild Cognitive Impairment
Authors: Johnson Brian B , Bolstad Britni A
Published: January 2025

Background

Patterns of human movement evolve as an individual experiences the progression from cognitively intact (CIN) to mild cognitive impairment (MCI) and finally dementia and Alzheimer’s Disease (AD). Quantification of movement with the goal of identifying MCI though step counts alone do not take into consideration the floor layout of a home. Cyclomatic complexity is an approach to normalizing differences in the individual’s living space to better predict the transition from CIN to MCI. This approach could be especially beneficial for organizations that manage large populations of individuals that prefer to age‐in‐place and hospital‐at‐home environments.

Method

Cyclomatic complexity is the sequence of movements through rooms rather than room transitions or step counts alone. For example, if two rooms are in a straight line (north to south) this has less cyclomatic complexity than two rooms that are diagonal (north to southwest). Cyclomatic complexity is represented as M = E − N + 2P where E is the amount of walking paths, N is the number of rooms, P is the total number of connected rooms (Khan & Jacobs). Movement entropy considers the decrease in the sequence rather than for separate rooms. Monitoring these variables with ambient sensors could provide groundbreaking insights on the quality of life of individuals as they age.

Result

Early studies have shown cyclomatic complexity to be a statically significant predictor of the progression of CI to MCI six months before diagnosis according to “Prediction of Mild Cognitive Impairment Using Movement Complexity” by Dr. Taha Khan and Dr. Peter G. Jacobs.

Conclusion

An estimation of movement to correlate the progression of MCI would benefit from using both sensor data on total step count in addition to cyclomatic complexity. Room transitions alone are unable to produce p < 0.05. Cyclomatic complexity adds potentially higher predictive value for MCI because it measures sequences of movement instead of quantity which varies depending on the individual’s home. Additional research is required to understand the technology requirements and data science to use cyclomatic complexity in the standard of care.
Clinical utility of 123I‐Ioflupane SPECT striatal binding for evaluating parkinsonism: a retrospective study of a dementia with Lewy bodies cohort
Authors: Maly Emily F , Leverenz James B , Lapin Brittany , Li Yadi , DiFilippo Frank A ,   U.S. Dementia with Lewy Bodies Consortium (DLBC)
Published: January 2025

Background

This study set to determine if 123I‐ioflupane SPECT striatal binding ratio (SBR) correlated with parkinsonian symptoms measured on Movement Disorder Society – Unified Parkinson’s Disease Rating Scale Part III (UPDRS‐III) in a dementia with Lewy bodies (DLB) cohort and if SBR measured at baseline could predict progression of parkinsonian symptoms over 2 years.

Methods

This is a retrospective cohort study using the U.S. Dementia with Lewy Bodies Consortium (DLBC) dataset. Sample group included 54 individuals with probable DLB or mild cognitive impairment with Lewy bodies (MCI‐LB). Participants had baseline 123I‐ioflupane SPECT scan analyzed with DaTQUANT and baseline UPDRS‐III examination; a subset of 25 participants had a 24‐month UPDRS‐III examination. Mean of the left and right SBR Z‐scores for the striatum, putamen, posterior putamen, and caudate were analyzed. A subset of 45 participants had CSF tested with [Amprion] α‐synulcein seed amplification assay (SAA).

Results

Multivariable linear regression models were used to predict 54 participants’ UPDRS‐III at baseline; this showed baseline SBRs are significant predictors of baseline UPDRS‐III scores with the caudate SBR having the strongest correlation (p=0.005). Multivariable linear regression models were used to predict 25 participants’ UPDRS‐III score at 24‐months; this showed baseline SBRs are significant predictors of 24‐month UPDRS‐III scores with the caudate SBR having the strongest correlation (p=0.009). When adjusting for baseline UPDRS‐III scores, SBRs are no longer significant predictors of 24‐month UPDRS‐III scores (p=0.36). When a multivariable logistic regression model was used to predict meaningful worsening in UPDRS‐III from baseline to 24‐months (defined as worsening by ≥ +5 points) the relationship was not significant (AUC=0.53). A sub‐analysis of the 45 participants with α‐synulcein SAA showed that presence α‐synulcein was associated with higher UPDRS‐III scores and lower SBRs.

Conclusion

Findings reveal a significant relationship between 123I‐ioflupane SPECT SBRs and motor parkinsonism in DLB as measured on UPDRS‐III. In DLB, 123I‐ioflupane SPECT scan, at time of diagnosis, could be used to confirm underlying dopamine deficiency in the context of clinical parkinsonism. Findings suggest baseline 123I‐ioflupane SPECT SBRs do not add value beyond baseline UPDRS‐III in predicting clinical progression of parkinsonism in 2 years.
Functional blocking of Varicella Zoster Virus prevents acquisition of Alzheimer’s disease‐like characteristics induced by reactivation of quiescent Herpes Simplex Virus Type 1
Authors: Cairns Dana M , Itzhaki Ruth F , Kaplan David L
Published: January 2025

Background

Hallmark features of AD are well defined, however, the generation of in vitro models of sporadic AD poses a significant challenge due to the complex, undefined etiology and slow progression of this disease. Herpes simplex virus type I (HSV‐1) is a pathogen that is gaining increasing attention as a potential causative agent in AD pathogenesis. HSV‐1 is a DNA virus that typically resides throughout the peripheral nervous system in a latent state. We have previously shown that HSV‐1 infection of human induced neural stem cells (hiNSCs) robustly mimic human disease with amyloid plaque–like formations, P‐tau accumulation, reactive gliosis, neuroinflammation, and diminished neural network functionality; completely in the absence of any exogenous mediators of AD. Further, we have demonstrated that quiescent HSV‐1 can be reactivated by various mechanisms, which also leads to AD‐like phenotypes. Varicella zoster virus (VZV) has been implicated in Alzheimer’s disease (AD), and vaccination against shingles, caused by VZV, has been found to decrease the risk of AD/dementia. Previous work in our lab demonstrated that hiNSCs infected with VZV did not show the main AD characteristics, Abeta and P‐tau accumulation, which HSV‐1 does cause, but did show gliosis and increased levels of pro‐inflammatory cytokines, suggesting that VZV’s action relating to AD/dementia is indirect. Strikingly, we found that VZV infection of cells quiescently infected with HSV‐1 causes reactivation of HSV‐1 and consequent AD‐like changes, including Abeta and P‐tau accumulation.

Methods

Given the established efficacy of vaccination against shingles in decreasing AD risk, we sought to determine whether neutralizing antibodies generated by vaccination, could attenuate the established effects of VZV in reactivating HSV‐1‐induced AD. We utilized hiNSCs latently infected with HSV‐1 and subsequently infected with VZV in the absence or presence of neutralizing VZV, then assessed expression of Abeta and P‐tau in vitro.

Results

We found that neutralizing antibody against VZV attenuated VZV infection and thus reactivation of HSV‐1 and associated downstream AD‐like phenotypes in hiNSCs.

Conclusions

These findings may provide mechanistic insight into the epidemiological evidence that VZV vaccination provides neuroprotection against AD/dementia.
The Sustainable Personalised Interventions for Cognition, Care, and Engagement (SPICE) Program: Interim analysis of a twelve week multicomponent intervention for people with dementia and care partners
Authors: D'Cunha Nathan M , Mitterfellner Rachael , Griffin Julie , Wiseman Lara , Isbel Stephen , Bail Kasia , Walker Ian , De Silva Sanduni , Whitting Sarah , Holloway Helen , Kosari Sam , Barrett Louise , Rutherford Kathleen , Bennett Michelle , Gibson Diane
Published: January 2025

Background

The Sustainable Personalised Interventions for Cognition, Care, and Engagement (SPICE) program was developed to address an identified gap in access to high‐quality integrated post‐diagnostic rehabilitation for people with dementia and their care partners in Canberra, Australia. The multicomponent intervention aims to maximise quality of life (QoL) and independence of people with dementia by increasing engagement in everyday and meaningful activities and promoting care partners' physical and mental well‐being.

Method

The SPICE program is a waiting‐list study design delivered by a multidisciplinary allied health team over twelve weeks. The five components are: 1) cognitive stimulation therapy; 2) carer support and capacity building; 3) physical activity; 4) Care of People with dementia in their Environments (COPE) program; and 5) dietary assessment and advice. Each group comprises up to seven people with dementia and their care partners. They engage in group activities twice weekly and receive the COPE program and dietary assessment and advice as a dyad. Outcome measures include QoL, neuropsychiatric symptoms, cognitive and physical function, and carer well‐being. Early feasibility of the program contributed to expansion of the study. Here, we report on the first six completed groups.

Result

Thirty‐eight people with dementia and 38 care partners attended group activities with 92% and 91% attendance, respectively. Participants completed 98% of COPE program appointments and 93% of dietary appointments. Pre‐ to post‐program improvements were observed in proxy‐reported QoL (p = 0.02), reduced neuropsychiatric symptoms (p<0.001) and carer distress related to these symptoms (p = 0.04), and reduced caregiving challenges (p<0.001). Both people with dementia and care partners improved in the Alternating Step Test (AST) (both; p<0.001), as did care partners in Timed Up and Go (TUG) (p = 0.04). Twenty‐six people with dementia and 26 care partners have completed follow‐up, improving from baseline to 24 weeks in self‐reported QoL of the person with dementia (p = 0.03), and reduced neuropsychiatric symptoms (p<0.01) and carer distress related to these symptoms (p = 0.02). Care partners maintained improvements in the AST (p<0.01) and TUG (p = 0.05).

Conclusion

Interim analysis suggests the SPICE program benefits people with dementia and their care partners. Further results are required to support continuation and expansion of the program.
Development of Individualized Cognitive Augmentation Regimen for Elderly (iCARE): Preliminary findings of a caregiver‐driven cognitive training for dementia in India
Authors: Kanmani Aparna S , Janakiprasad Keshav K , PT Sivakumar , Mathuranath PS
Published: January 2025

Background

With increased for promoting neuroplasticity in older adults through Cognitive training (CT), the study aimed to develop culturally relevant caregiver‐driven model of CT for dementia called the Individualized Cognitive Augmentation Regimen for Elderly (iCARE).

Method

The study has three phases‐

1. Development Phase‐ Included a) literature review, b) item generation, c) expert rating, d) field trial (n = 3), and e) feedback and modification. The module is designed as a flip book primarily targeting eight cognitive domains. A unique method of empowering caregivers (family or professional) as co‐therapists was used to deliver the intervention on adequate receiving training.

2. Pilot Phase ‐ A quasi‐experimental research design was used to recruit patients (n = 8) diagnosed with mild‐moderate dementia (DSM V criteria) from a clinical setting. The eligible participants were engaged as dyads (1 patient + 1 caregiver) and received either Treatment as usual (TAU) or iCARE program (1:1 ratio) for a duration of 5 weeks. They were assessed at three time points (baseline, post‐intervention, and 1‐month follow‐up).

3. Main Phase – The modified program was administered on 32 dyads (16 Intervention, 16 TAU) meeting the inclusion and exclusion criteria using the same protocol. The NIMHANS neuropsychological battery for elderly (NNB‐E) was used to determine the neuropsychological profile of the patient along with rating scales to track cognitive symptoms, quality of life, activities of daily living, behavioural/psychological symptoms, caregiver health and burden.

Result

The study revealed positive results in task‐related performance, outcome variables, and functional changes. The neuropsychological profiles post‐iCARE demonstrated improvement in attention, working memory, fluency, verbal recognition and logical and visual memory. Compared to TAU, enhancement was noted in quality of life, independence in daily activities, and symptom severity. Caregivers also reported advancement in confidence, error detection, self‐correction, communication and insight. The caregivers' high rating for feasibility of iCARE make it suitable for Indian population. Qualitative evidences of the same shall be presented.

Conclusion

The iCARE program intends to support families learn a better‐quality home‐based management of dementia. The method of using interactive materials and caregivers as active co‐therapists is recommended to address cognitive decline in dementia.
Event‐related Theta Phase Coherence differ between stable and progressive MCI: aTwo‐Year Follow‐up study
Authors: Özbek Yağmur , Yener Görsev
Published: January 2025

Background

Mild cognitive impairment (MCI) is viewed as a transitional stage between normal aging and Alzheimer's disease (AD), serving as a pathological precursor to AD. Longitudinal studies indicate an annual conversion rate from MCI to AD of 10‐15%. Our previous studies have shown decreased coherence values in visual event‐related slow frequency bands including theta frequency. This study aimed to compare event‐related theta inter‐trial phase coherence (ITC) in two groups of MCI, stable or progressive MCI, and cognitively unimpaired (CU) seniors, during a two‐year follow‐up.

Method

Out of 33 individuals with MCI, 14 of the MCI patients progressed into AD dementia (ADD) at a two‐year follow‐up (progressive MCI: pMCI), whereas 19 MCI patients remained stable (stable MCI: sMCI). A total of 34 cognitively unimpaired (CU) seniors were included in this study. Classical visual oddball paradigm was used to elicit event‐related (ER) oscillations. Continuous Wavelet Transformation was used for intertrial phase locking (Intertrial Coherence) analyses.

Result

Mixed‐design ANOVA analysis showed TIME x LOCATION x GROUP interaction effect in theta ITC. Posthoc analyses indicated baseline temporal theta ITC values of CU were higher than sMCI (p = 0.028) and pMCI (p = 0.014). In addition, follow‐up measurements of central theta ITC of CU were higher than pMCI (p = 0.033), and parietal theta ITC of CU was higher than pMCI (p = 0.008) and sMCI (p = 0.002). It was found that the baseline temporal ITC values of CU (p = 0.018) and the baseline parietal theta ITC values of sMCI (p = 0.033) were higher compared to follow‐up measurements.

Conclusion

Among the classical frequency bands, the stimulus‐locked ER theta phase reflects best about temporal processes of cortical functions for the MCI patients who convert to dementia. Furthermore, the increased ER theta coherence at the stable MCI level returns to the normal values at the later stages of MCI (pMCI). Our findings are in line with the hyperconnectivity seen at the stable MCI stage, even before becoming progressive MCI. Theta ITC may provide electrophysiological cues for displaying clinical stages during MCI period.
Association of Alzheimer’s disease polygenic risk score with concussion severity and recovery metrics
Authors: Dybing Kaitlyn M , McAllister Thomas W , Wu Yu‐Chien , McDonald Brenna C. , McCrea Michael A. , Broglio Steven P. , Pasquina Paul F. , Brooks M. Alison , Mihalik Jason P. , Guskiewicz Kevin M , Giza Christopher C. , Goldman Joshua , Duma Stefan , Rowson Steve , Svoboda Steven , Cameron Kenneth L. , Houston Megan N. , Campbell Darren E. , McGinty Gerald , Jackson Jonathan , Risacher Shannon L. , Saykin Andrew J. , Nudelman Kelly N.
Published: January 2025

Background

Shared genetic risk between Alzheimer’s disease (AD) and concussion may help explain the association between concussion and elevated risk for dementia. However, there has been little investigation into whether AD risk genes also associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) and APOE genotypes to investigate associations between AD genetic risk and concussion severity/recovery in the NCAA‐DoD Grand Alliance CARE Consortium (CARE) dataset.

Method

There were 1,917 injuries in the dataset upon project initiation. After removing repeated injuries, related participants, and those without genetic/outcome data, we had 931 participants. Outcomes were number of days to return to play (RTP) as a recovery measure, and four severity measures (scores on SAC and BESS, SCAT symptom severity and total number of symptoms). We calculated PRS using a published score (de Rojas et al., 2021) and performed a linear regression (MLR) of RTP by PRS in normal (<24 days) and long (>24 days) RTP subgroups. We then compared severity measures by PRS using MLR. Next, we used t‐tests to examine outcomes by APOE genotype in military and civilian subgroups. We also performed chi‐squared tests of RTP category (normal vs. long) by APOE genotype. Finally, we analyzed outcomes by PRS in European or African genetic ancestry subgroups using MLR.

Result

Higher PRS was associated with longer injury to RTP interval in the normal RTP (<24 days) subgroup (estimate = 0.0412, SE = 0.182, p = 0.0237). 1 SD increase in PRS resulted in a 0.412 day (9.89 hours) increase to the interval. This may be clinically meaningful in the collegiate athlete environment. We did not identify any other significant differences.

Conclusion

Our preliminary results provide limited evidence for an impact of AD PRS on concussion recovery, though the pattern was inconsistent and its clinical significance is uncertain. Future studies should attempt to replicate these findings in larger samples with longer follow‐up using PRS calculated from multiple/diverse populations, which will be especially relevant for diverse datasets like CARE.
Brain Banking in the United States and Europe: Importance, Challenges, and Future Trends
Authors: Danner Benjamin , Gonzalez Angelique D. , Corbett William Cole , Alhneif Mohammad , Etemadmoghadam Shahroo , Parker‐Garza Julie , Flanagan Margaret E
Published: January 2025

Background

In recent years, brain banks have become a valuable resource for examining the molecular underpinnings of various neurological and psychological disorders such as Alzheimer’s disease and Parkinson’s disease; however, the availability of brain tissue has significantly declined. Proper collection, preparation, and preservation of post‐mortem autopsy tissue are essential for optimal downstream brain tissue distribution and experimentation. Collaborations between brain banks through larger networks such as NeuroBioBank with centralized sample request mechanisms promote tissue distribution where brain donations are disproportionately lower. These collaborations would also help standardize the donation and sample preparation processes and enable the distribution of knowledge and information amongst neuroscientists. Implementing ethical measures during donation enhances the responsible conduct of scientific studies and cultivates trust among donors. Education and outreach programs that foster collaboration between hospitals, nursing homes, neuropathologists, and other research scientists can alleviate concerns among potential brain donors. Furthermore, ensuring that biorepositories accurately reflect the true demographics of communities will result in research data that reliably represents populations. Therefore, there is a need for initiatives to enhance the sustainability and efficacy of brain banks, fostering an environment that aligns with the evolving needs of scientists and researchers.

Method

This review involved a comprehensive search of Google, Google Scholar, and PubMed databases. Relevant English articles and information from websites pertaining to brain banking in the United States and Europe were extracted for thorough examination, up until November 2023.

Result

Brain autopsy rates have had a steady decline from 41.1% in 1964 to less than 5% in many hospitals today. Additionally, published cost estimates of collecting a postmortem brain approximate the cost to be between $10,000 and $30,000 USD. With brain tissue scarcity posing an utmost problem to many neuropathologists and scientists, increasing standard operating procedures, centralization of Brain banks will serve to combat the decline.

Conclusion

Successful implementation of these initiatives, such as enhancing collaboration between intra‐institutional and inter‐institutional brain banks alongside integration of innovative technologies and proactive efforts to improve brain donations and storage will grant scientists improved access to brain tissue. This will then facilitate a deeper understanding of the neurological diseases that impact millions.
Connectivity to epicenters of tau accumulation contributes to regional synaptic loss in Alzheimer’s disease
Authors: Luan Ying , Wang Weiyi , Guan Yihui , Franzmeier Nicolai , Xie Fang , Ewers Michael
Published: January 2025

Background

Alzheimer’s disease (AD) is associated with substantial synaptic loss potentially due to synaptotoxicity of fibrillar tau, but the association between tau deposition and synaptic loss remains unclear. Based on previous observations that pathology spreads preferentially between closely connected regions, we tested in the current multi‐PET tracer study the hypothesis that synaptic loss propagates to regions closely connected to epicenters of high tau accumulation.

Method

We assessed 18F‐SynVesT‐1 PET as a measure of synaptic vesicle glycoprotein 2A (SV2A), and 18F‐flortaucipir tau‐PET in fourty‐five 18F‐florbetapir‐PET‐positive (Aβ+) subjects with MCI or AD dementia, and 23 cognitivly normal (CN) Aβ‐ controls. All PET scans were spatially normalized and parcellated into 200 ROIs. Adopting our previously established connectivity‐based prediction model (Franzmeier et al. Nat Commun 2020), we computed tau‐epicenter connectivity maps by projecting regions of highest tau‐PET SUVR (top 10% of group‐average tau‐PET ROIs) onto a normative resting‐state fMRI derived connectivity template from the Human Connectome Project. The tau‐epicenter connectivity map was projected onto the group‐average synaptic PET ROI w‐scores (standardized SUVR difference between Aβ+ vs Aβ‐ group) to test in linear regression analysis, epicenter connectivity as a predictor of synaptic PET w‐scores in connected ROIs. As a control, we conducted an additional regression analysis, using this time connectivity to cold spots of tau‐accumulation (10% of ROI with lowest tau‐PET uptake) instead of epicenter‐connectivity as a predictor. We repeated the analyses at the subject level, controlling for the effect of age, gender, clinical diagnosis and global amyloid‐PET uptake.

Result

Higher functional connectivity to the tau‐epicenter was associated with lower synaptic PET binding in the connected ROIs (β = ‐0.380, p < 0.001, Figure 1A). In contrast, functional connectivity to the tau coldspot ROIs was associated with more preserved synaptic PET binding in the connected ROIs (β = 0.396, p < 0.001, Figure 1B). Subject‐level analysis showed consistent findings (Figure 2 for tau‐epicenters).

Conclusion

Synaptic loss in AD occurs in a connectivity‐dependent manner, where closer functional connectivity to regions of high tau is associated with stronger loss in synaptic PET. Putative underlying mechanisms are the higher tau in tau‐epicenter connected regions or functional decline in the connected regions.
Relationships Between Retinal Amyloid Imaging and Amyloid PET in the A4 Trial
Authors: Rissman Robert A. , Ngolab Jennifer , Donohue Michael C. , Belsha Alison , Salazar Jennifer , Cohen Paula , Jaiswal Sandhya , Tan Veasna , Aggarwal Neelum T. , Alber Jessica , Johnson Ken , Jicha Gregory A , van Dyck Christopher H. , Lah James J. , Salloway Stephen , Rafii Michael , Aisen Paul S. S. , Sperling Reisa A
Published: January 2025

Background

Alterations to the retina manifest in patients diagnosed with neurodegenerative diseases such as Alzheimer’s disease (AD). Retinal imaging techniques open the possibility for non‐invasive evaluation of AD pathology. Clinically AD diagnosed patients exhibit retinal amyloid deposits. Few studies monitoring preclinical individuals exist, limiting the assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection.

Method

We compared retinal and cerebral amyloid in clinically normal individuals who screened positive for amyloid through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) as well as a companion cohort of individuals who were negative on amyloid by amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from a small subset of participants from both studies to determine retinal amyloid deposition at baseline.

Result

Participants from the A4 trial exhibited a greater number of retinal spots compared to those from the LEARN study. We report a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr).

Conclusion

The results of this small pilot study support the use of retinal fundus imaging for detecting amyloid deposition that is correlated with brain amyloid PET SUVr. A larger sample set is under analysis currently to fully ascertain the relationship between amyloid PET and retinal amyloid both cross‐sectionally and longitudinally.
The Predictive Value of Structural OCT in Preclinical AD
Authors: Alber Jessica
Published: January 2025

Background

Research shows that structural retinal changes, measured via spectral‐domain optical coherence tomography (SD‐OCT), are sensitive diagnostic biomarkers in AD. Our recent work aims to validate retinal biomarkers as risk biomarkers in preclinical AD. We compared retinal layer thickness to plasma ptau217 (a valid measure of Aβ pathophysiology in preclinical AD) to determine the predictive value of structural retinal changes in preclinical AD.

Method

A total of 120 cognitively unimpaired (CU; CDR=0, MoCA>26) older adults aged 55‐80 underwent SD‐OCT imaging. Plasma samples were analyzed with the Simoa ALZpath pTau 217 assay. Multinomial logistic regression models, with age, APOE E4 status and first degree family history as covariates, were used to assess the predictive value of each retinal layer on plasma ptau217 concentrations, with emphasis on layers that have shown thinning in clinical AD (macular retinal nerve fiber layer, mRNFL; ganglion cell layer, GCL; inner plexiform layer, IPL). Additional iterative models added mRNFL, then GCL and IPL, to assess the combined predictive value of the retinal layers. ROC analysis with assay‐specific plasma ptau217 cut‐off .495 was used to determine how well each retinal layer and/or the retinal layers combined predicted preclinical AD status. Partial correlations (controlling for age) were performed to determine the relationships between individual retinal layer thicknesses and plasma ptau217.

Result

There were significant positive correlations between the thickness of the inner inferior and superior GCL and IPL and plasma ptau217 (all p<.05). Inner inferior and superior mRNFL and GCL thickness were significant predictors of plasma ptau217. The model that had the best performance included age, APOE status, first degree family history, and the inner inferior and superior thickness of the mRNFL, GCL, and IPL, with AUC = .90, (95%CI = .86‐.93, p<.01).

Conclusion

Retinal thickness, measured by SD‐OCT, could be a useful screening tool to identify those at high risk for preclinical AD who may benefit from more invasive or expensive neuroimaging for confirmation. Longitudinal follow‐up is ongoing to determine the prognostic value of SD‐OCT in predicting conversion to symptomatic AD.
Plasma ptau181 levels at baseline and over time according to amyloid status and SCD in SILCODE cognitively unimpaired older adults
Authors: Shao Kai , Kuhn Elizabeth , Hu Xiaochen , Yan Shaozhen , Chen Zhigeng , He Beiqi , Jiang Xueyan , Li Ruixian , Wang Xuanqian , Wei Min , Wei Yongzhe , Yang Jie , Yu Xianfeng , Zhang Mingkai , Zhang Liang , Lu Jie , Wagner Michael , Han Ying ,   SILCODE study group
Published: January 2025

Background

Cognitively unimpaired (CU) older adults with abnormal levels of β‐amyloid (Aβ) deposition are considered in the preclinical stage of Alzheimer’s disease (AD) and, when combined with the subjective cognitive decline (SCD), are proposed as the stage 2 AD in the NIA‐AA framework. Here, we aim to investigate whether neuropathologic deterioration increases in early stages, particularly in stage 2 AD.

Method

We included 341 CU participants over 50 years of age from the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. SCD was defined based on baseline cognitive complaints with associated concern/worry, whereas normal control (NC) did not express any concern/worry. Aβ status was defined based on amyloid‐PET or, if not available, on plasma Aβ42/40 ratio. All selected participants had available plasma phospho‐tau181 (ptau181), and were divided into four groups according to SCD combined with baseline Aβ positivity. General linear models and linear mixed‐effect models were performed to determine whether ptau181 levels differed between groups (i.e., NC.Aβ‐, SCD.Aβ‐, NC.Aβ+, SCD.Aβ+) at baseline and over time.

Result

At baseline, the four groups were significantly different in terms of ptau181 levels (p=0.001), with the SCD.Aβ+ group having higher levels than NC.Aβ‐ (p=0.004) and SCD.Aβ‐ (p=0.003), but not different from NC.Aβ+ (p=0.63). In the smallest sample of 81 CU with available follow‐up for ptau181 (i.e., 15 NC.Aβ‐, 35 SCD.Aβ‐, 8 NC.Aβ+, 23 SCD.Aβ+), we replicated the baseline differences (p=0.037). Longitudinal analysis showed that ptau181 levels changed differently between groups over time (p=0.016), with SCD.Aβ+ showing a faster increase over time than SCD.Aβ‐ (p=0.011).

Conclusion

Our results showed that participants with stage 2 AD (SCD.Aβ+) have a higher ptau181 burden at baseline and increasing plasma ptau181 levels over time in a Chinese sample. This suggests that this group is at higher risk for neuropathologic changes, although no differences were found with stage 1 (NC.Aβ+). It should be noted that sample sizes for longitudinal analyses were small, especially for NC, which may partly explain this lack of differences between stages 1 and 2 AD. The SILCODE follow‐up is ongoing, and we plan to test this hypothesis at a later stage.
Chalcone derivate as a promising candidate for treating Alzheimer’s disease
Authors: Haas Murillo Orsatto , Ruaro Thaís C , Gosmann Grace , Zimmer Aline R.
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive and multifactorial neurodegenerative disease that still has no cure. Different pathological processes contribute to the disease’s development, such as the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles (NFTs), glutamatergic excitotoxicity, oxidative stress, and neuroinflammation1. Chalcones are polyphenolic compounds of natural origin with a wide range of biological activities2, and emerging studies have reported neurotrophic activity, anti‐inflammatory and antioxidant effects, and the inhibition of Aβ aggregation. In this study, we developed a series of innovative molecules based on chalcones and evaluated their cytotoxicity and neuroprotective effects in silico and in vitro experimental platforms.

Methods

The MarvinSketch and SwissADME platforms were used to predict the drug‐like properties of the compounds and their ability to permeate the blood‐brain barrier (BBB). The in vitro assays of the 19 compounds were performed in C6 astroglial and VERO cell lines to assess their cytotoxicity. After that, their neuroprotective effects were evaluated against oxidative and glutamatergic insults in the C6 astroglial cell line. The 3 most promising compounds were tested in a primary culture of astrocytes from the cerebral cortex of a neonatal Wistar rat, and their ability to protect the cell from neuroinflammatory insult (LPS) was evaluated.

Results

The in silico results indicated that all compounds presented satisfactory drug‐like properties and low or no cytotoxicity. Among tested compounds in in vitro assays, the most promising candidate was CHA 16. It showed a suitable oral bioavailability and a high potential to cross the BBB in silico assays, low cytotoxicity, and a neuroprotective effect against the oxidative and glutamatergic insults in C6 astroglial cells and against the inflammatory insult in primary astrocyte cells. In addition, CHA 16 displayed significant astro‐trophic effects in both cells tested.

Conclusion

The compound CHA 16 protected the astrogial cells from oxidative, neuroinflammatory, and glutamatergic toxicity. Together with the high potential for oral use and passage through BBB, it is a promising candidate for clinical testing targeting AD treatment.

References:

1 Therriault, J. et al. Trends in Molecular Medicine. Volume 28,9:726‐741,

2 GOMES, M.N. et al. Chalcone Derivatives: Promising Starting Points for Drug Design. Molecules, 22:1210, 2017
Exploring the correlation between dietary pattern and cognitive functioning in an aging rural Indian population
Authors:   Aishwarya B H , Sahadevan Pravin , Anilkumar Shobha , Rai Pooja , Sundarakumar Jonas S.
Published: January 2025

Background

Studies on the relationship between diet and cognition have been predominantly from urban and Western populations. However, dietary patterns could vary considerably between populations and the rural Indian population has been grossly underrepresented in this research We aim to investigate the association between dietary pattern and cognitive functioning in an aging, rural Indian population.

Method

The current study utilized a cross sectional design, comprising cognitively healthy participants from the SANSCOG (Srinivaspura Aging Neuro Senescence and COGnition) cohort, an ongoing, aging, community‐based cohort study in a rural, southern part of India, recruited through an area sampling strategy. A total of 3,095 dementia‐free participants, aged 45 years and above, who had completed a dietary assessment questionnaire and underwent a detailed cognitive assessment were included in the study. Cognitive performance was evaluated using a culturally adapted computerized neurocognitive test battery, COGNITO (Computerized assessment of adult information processing), which assesses cognitive domains such as attention, memory, language, visuospatial ability and executive functioning. A composite z score was derived from the average of the individual cognitive domain scores. A linear regression model was employed to investigate the association between dietary pattern and cognitive functioning after adjusting for potential confounders.

Result

Our findings showed that participants with lesser fluid intake (3 cups/day [β: ‐0.058, 95%CI: ‐0.106, ‐0.010] and 3‐5 cups/day [β: ‐0.063, 95%CI: ‐0.102, ‐0.025]) had poorer cognitive performance when compared with those with fluid intake of more than 5 cups/day. In addition, consumption of meat and fish was associated with poorer cognitive performance [β: ‐0.079, 95%CI: ‐0.153, ‐0.004] compared to participants who do not consume meat and fish. Further, we did not find any significant association of the other dietary variables that were studied, such as like number of meals per day, consumption of fruits and vegetables, eggs and legumes with cognitive performance.

Conclusion

Our study highlights the important influence of dietary pattern on cognition. Comprehensive dietary assessments and a longitudinal study design are necessary to make any robust conclusions regarding the precise relationship between dietary pattern and cognitive functioning.
The effects of blood‐brain barrier permeability on Alzheimer’s disease plasma biomarkers and their impact on clinical performance
Authors: Pornteparak Nattanich , Thanapornsangsuth Poosanu , Pongpitakmetha Thanakit , Ongphichetmetha Tatchaporn , Rianaree Juthamas , Luechaipanit Watayuth , Haethaisong Thanaporn , Chongsuksantikul Adipa , Likitjaroen Yuttachai , Hemachudha Thiravat
Published: January 2025

Background

The validation of blood‐based biomarkers presents a promising role in Alzheimer's disease (AD) diagnosis owing to their accessibility and diminished invasiveness. However, despite awareness of confounding factors like kidney function, inaccuracies persist in AD diagnosis using plasma p‐tau. Notably, diverse conditions that modify blood‐brain barrier (BBB) permeability have been linked to high plasma p‐tau levels, irrespective of AD pathophysiology.

Methods

Data were sourced from pooling participants from preceding studies on individuals with encephalopathy and from patients attending a memory clinic, where both plasma and cerebrospinal fluid (CSF) were acquired. Stratifying participants based on binary plasma and CSF p‐tau181 results (using independently validated cut‐offs), the study compared the CSF/plasma albumin quotient (qAlb) between false positive and non‐false positive groups. Univariable linear regression predicting CSF p‐tau181 from plasma p‐tau181 was employed, facilitating the quantification of CSF p‐tau residuals for each participant. The correlations between residuals and qAlb as well as residuals and kidney were examined. A multivariable logistic regression model incorporating qAlb and plasma p‐tau181 to predict AD CSF profile was developed using encephalopathy participants and tested on the memory clinic patients.

Results

A total of 147 participants were included. The qAlb is significantly elevated in the plasma p‐tau false positive group (0.0066 vs. 0.0049, p=0.04658). A notable negative correlation exists between qAlb and CSF p‐tau residuals (Spearman rho = ‐0.0986, p = 0.0347), while no correlation was observed between kidney function and CSF p‐tau residuals (Spearman rho = ‐0.1806, p = 0.2515). Plasma p‐tau181 and qAlb predict AD in the memory clinic with the AUC of 0.78 (95% CI 0.64‐0.92), not different from using p‐tau alone (AUC 0.7778 vs 0.7759, p=0.8626).

Conclusion

BBB permeability influences the prediction of CSF p‐tau181 from plasma p‐tau181, notably leading to excessive level of plasma p‐tau (ie. false positives). Conversely, in evaluating the effectiveness of integrating qAlb with plasma p‐tau181 for the prediction of AD CSF profiles in clinical contexts, no difference from plasma p‐tau alone was observed. Future investigations should explore whether other biomarkers of BBB influence plasma biomarkers in a similar direction and are useful in identifying potential incorrectly classified patients.
Cavum Septum Pellucidum (CSP) as a Neuroimaging Signature of Head Impact Exposure compared to Non‐exposed Patients with Neurodegenerative Disease and Controls
Authors: Kamps Suzie , Hempel Hugo L. , van Amerongen Suzan , de Bruin Hannah , van der Linden Fleur H.C. , Barkhof Frederik , Scheltens Philip , Ossenkoppele Rik , Vijverberg Everard G.B.
Published: January 2025

Background

Cavum Septum Pellucidum [CSP] is commonly observed on neuroimaging in individuals exposed to repetitive head impacts [RHI] and in post‐mortem examination in Chronic Traumatic Encephalopathy [CTE]. A CSP is proposed as a potential biomarker for CTE, yet prevalence across neurodegenerative diseases and its clinical implications are largely unknown. We assessed CSP prevalence and clinical associations in RHI‐exposed individuals in comparison to veterans with a history of traumatic brain injury [TBI], individuals with a neurodegenerative disease (i.e. Alzheimer’s Disease [AD] or Frontotemporal dementia [FTD]) and Cognitively Unimpaired individuals [CU].

Method

The group‐of‐interest, i.e., individuals exposed to RHI in contact sports or military service (n=66), was compared against age‐ and sex‐matched ADNI‐DOD participants with TBI (n=62) and non‐exposed participants of the Amsterdam Dementia Cohort (AD, n=30; FTD, n=25; CU, n=25). Structural 3D brain MRI scans were visually rated on CSP grade (ranging 0‐4, Figure 1) according to established criteria by two independent raters without access to clinical information. A CSP scored at least grade 2 was considered abnormal. If scores between raters differed, scans were discussed to reach consensus. Inter‐rater reliability was assessed with Cohens’ weighted Kappa (κ). We investigated group differences in CSP grade as well as associations between CSP grade and neuropsychiatric symptoms (using the Neuropsychiatric Inventory [NPI]) and CTE probability (using the Traumatic Encephalopathy Syndrome [TES] criteria).

Result

Inter‐rater reliability was substantial (κ=0.712). Prevalence of an abnormal CSP differed between groups (χ2=11.72, p=.020). An abnormal CSP was observed most often in the RHI group (43%), followed by TBI (31%, OR=0.589, p=.158), and significantly less in AD (16%, OR=0.255, p=.014), FTD (17%, OR=0.267, p=.029), and SCD (14%, OR=0.222, p=.012) compared to RHI (Figure 2). Across groups, CSP grade was not associated with severity of neuropsychiatric symptoms (F=1.7, p=0.151). An abnormal CSP was observed more in RHI‐exposed individuals with probable (57%) or possible (55%) CTE compared to suggestive of CTE (36%) or no TES (36%).

Conclusion

A CSP was more prevalent in RHI‐exposed individuals and veterans with TBI compared to patients with a neurodegenerative disease or CU individuals. Presence of a CSP on MRI may be indicative of head impact exposure, especially repetitive impacts.