bluuebunny/crossref_metadata_2025 huggingface dataset:
Virulent Porphyromonas gingivalis as the root cause of chronic inflammation‐a Chronic Oral Health Perspective
Authors: Sindelar Dan
Published: December 2023

Oral health professionals are the forefront of preventing and treating not only dental and periodontal diseases, but also a growing list of systemic conditions associated with specific periodontal pathogens such as P. gingivalis (Pg). The oral‐systemic connection offers dental professionals an opportunity to positively influence patients’ overall health. Armed with the ability to transform its own environment and the entire periodontal microbiome, as well as modify the host response, the influence of Pg extends beyond the oral cavity. Beyond the neuroinflammatory effects discussed in this session it is capable of both releasing complex virulence factors/toxins and translocating and invading distant tissues and organs and is involved in the pathogenesis of systemic diseases including cardiovascular disease, atherosclerosis, hypertension, myocarditis, and myocardial infarction. This periodontal pathogen also impacts autoimmune diseases including rheumatoid arthritis; neurodegenerative diseases such as Alzheimer’s disease and AD‐related brain atrophy; several cancers‐oral, esophageal, and pancreatic; and metabolic diseases such as diabetes mellitus. Pg by limiting the complement cascade and restraining leukocyte death by activating and exploiting the C5a‐receptor signaling pathway. Another viable conduit in systemic dysbiosis and immune dysfunction is the translocation of Pg with its microbiome‐altering abilities and its coaggregation pathobiont actions found in the gut flora. Studies on murine models that introduced Pg into the gut demonstrated an altered intestinal microflora and increased manifestation or aggravation of liver disease, arthritis, including an increase in the production of proinflammatory cytokines observed at both the intestinal and extra‐intestinal levels. Dental professionals will most likely be one of the major healthcare delivery systems to bring a paradigm shift in healthcare and medicine using novel companion diagnostics and treatments to early screening and treatment of virulent Pg infections in the general population thereby greatly reducing the onset of multiple major systemic inflammatory driven chronic diseases. Dental professionals will most likely be one of the major healthcare delivery systems to bring a paradigm shift in healthcare and medicine by using novel companion diagnostics and treatments to early screening and treatment of virulent Pg infections in the general population thereby greatly reducing the onset of multiple major systemic inflammatory driven chronic diseases.
Memory alteration test (M@T) is correlated with CSF biomarkers and neurodegeneration in patients with aMCI and AD in a low‐and‐middle‐ income country
Authors: Custodio Nilton , Malaga Marco , Montesinos Rosa , Chambergo‐Michilot Diego , Baca Fiorella , Carbajal Juan C , Huilca Jose , Herrera‐Perez Eder , Lira David , Diaz Monica M , Lanata Serggio
Published: December 2023

Background

As new therapies become available, early detection of Alzheimer’s disease (AD) becomes increasingly important. However, the use of biomarkers or advanced imaging has not been fully implemented in low‐ and ‐middle income countries (LMICs), especially in Latin America. Given that brief cognitive tests (BCTs) are widely available and easy to administer, we evaluated the capacity of the AD‐focused BCT, the Memory Alteration Test (M@T), to detect AD, neurodegeneration markers in MRI, and its correlation with CSF biomarkers.

Method

This is a secondary analysis from a previously published cohort of 63 controls, 53 amnestic MCI (aMCI), and 69 AD patients. They underwent testing with the M@T and a complete neuropsychological battery. Total‐tau (t‐tau), phosphorylated tau (p‐tau) and β‐amyloid in CSF were measured in all included patients. Neurodegeneration was determined by Medial Temporal Atrophy (MTA) score in MRI. We used Receiver‐Operator Curves to determine the discriminative capacity of the total M@T score as well as its subdomains. We used the Pearson coefficient and performed a linear regression between total score and CSF biomarkers.

Result

The M@T score had an AUC of 0.994 to discriminate between controls and cognitively impaired (aMCI or AD) patients, and an AUC of 0.98 to differentiate between aMCI and AD patients. Free‐recall and cued recall had the highest AUCs of all subdomains. Total score was strongly correlated with t‐tau (‐0.77) and p‐tau (‐0.72), and moderately correlated with β‐amyloid (0.66). The AUC for discrimination of neurodegeneration was 0.87.

Conclusion

The M@T brief cognitive test had excellent discrimination of MCI and AD patients in an LMIC. It was also strongly correlated with CSF biomarkers and had good discrimination of Neurodegeneration. The recall sub‐domains presented the highest diagnostic capacity. Its use as a screening tool could allow LMICs to enrich samples of patients who may benefit from new available therapies.
Chronic traumatic encephalopathy in former college football playing brain donors
Authors: Hong Cindy , Abdolmohammadi Bobak , Martin Brett M , Palmisano Joseph N , Alvarez Victor E. , Huber Bertrand R. , Tripodis Yorghos , Stein Thor D. , Alosco Michael L , McKee Ann C. , Mez Jesse B.
Published: December 2023

Background

Chronic traumatic encephalopathy (CTE) is neurodegenerative disease associated with a history of repetitive head impacts (RHI). The majority of CTE cases have been reported in former contact sport athletes, including American football players. In 2017, a case series from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank reported that 48 of the first 53 donors with college football as their highest level of play had CTE. Here we present updated numbers of former college football players with CTE in the UNITE Brain Bank and compare them to former college football players without CTE. We hypothesized that increasing CTE stage would be associated with dementia and increasing scores on clinical scales of informant reported symptoms.

Method

Brain donors from the UNITE Brain Bank with college football as their highest level of play were included. CTE neuropathological diagnosis and staging (0‐IV; 0 = no CTE, IV = most severe) were assessed using validated criteria. Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS), activities of daily living (Functional Activities Questionnaire, FAQ), and neurobehavioral dysregulation (BRIEF‐A Behavioral Regulation Index, BRI). Consensus dementia diagnoses were made by expert clinicians. Multivariable regression models examined associations between CTE stage, dementia, and each clinical scale, controlling for age at death, racial identity, education, and duration of football play in years.

Result

Among 319 donors with college football as their highest level of play (median age at death = 64.0; IQR = 47‐77), 222 (69.5%) had CTE. Among those with CTE, 44 (19.8%) were stage I, 47 (21.2%) were stage II, 79 (35.6%) were stage III and 52 (23.4%) were stage IV. Among those with CTE, 122 (55.0%) were demented and 123 (61.5%) and 131 (70.8%) had clinically meaningful elevations on the FAQ and BRI respectively. CTE stage was significantly associated with having dementia (OR = 1.37; 95%CI:1.08‐1.72) and with more symptoms on the CDS (beta = 5.04; 95%CI:1.41‐8.66) and FAQ (beta = 1.12; 95%CI:0.38‐1.86), but not the BRI. Effect estimates were larger after removing donors with non‐CTE neurodegenerative pathology.

Conclusion

Among former college football playing brain donors, CTE pathology was very common. CTE stage was significant associated with dementia history and symptoms on clinical scales.
Epigenetic Modulation Through KAT5/HDAC2 Regulates Synaptic Genes in a Disease‐State Specific Manner
Authors: Wiley Jesse C , Yeboah Fred , Cary Gregory A. , Frankowski Harald , Heath Laura M , Levey Allan I. , Greenwood Anna K , Carter Gregory W , Young Jessica E.
Published: December 2023

Background

The balance between histone acetylation and deacetylation by lysine acetyltransferases (KATs) and histone deacetylases (HDAC) plays a central role in neurodegeneration. In this work, we leverage the informatics infrastructure developed for TREAT‐AD, to align epigenetic regulation from two different models: the KAT5 knockout mouse and HDAC2 knockdown iPSC‐derived neurons of control and FAD genetic lineages.

Method

The KAT5 knockout mouse differential expression data derived from the CA1 of the hippocampus was compared to three groups: 1) human late onset Alzheimer’s disease (LOAD), 2) the 5X FAD mice and 3) human FAD patient transcriptomic data. In each comparison, the data was assessed in the context of the biological domains (19 core AD endophenotypes computationally defined for the TREAT‐AD bioinformatics pipeline). The KAT5 data are compared to the differential expression data derived from WT and FAD lines of iPSC‐derived neurons with or without HDAC2 knockdown (KD) post‐differentiation.

Result

The biological domain focused analysis found a consistent modulation of synaptic and immune genes across models. Interestingly, there is a statistically significant correlation between down‐regulated synaptic genes in the KAT5 knockout mouse data and human LOAD differential expression observed in the 1700 brains of transcriptomic data and 1100 brains of proteomic data analyzed for TREAT‐AD and concomitantly identified in early stage pseudotemporal models of AD. Not surprisingly, there is better correlation between the KAT5 KO mouse and the 5X FAD mice, with the human FAD data falling in between these comparisons. The examination of the FAD and WT iPSC‐derived neurons with and without HDAC2 KD, demonstrates that HDAC2 KD ameliorates the down‐regulation of synaptic genes in the FAD neurons, but appears to have the opposite effect in WT human neurons.

Conclusion

The comparison of the two systems of epigenetic regulation suggest that KAT5 and HDAC2 exert opposite effects upon synaptic gene expression. However, the observation that decreasing HDAC2 levels increases synaptic gene expression in FAD neurons but decreases synaptic gene expression in normal healthy neurons suggest that there is an optimal chromatin state associated with maximal synaptic gene expression, and that too much or too little histone acetylation may impair synaptic homeostasis.
[18F]‐D3FSP amyloid‐β PET imaging in elderly adults and Alzheimer’s disease
Authors: Li Anqi , Zhao Ruiyue , Zhang Mingkai , Sun Pan , Cai Yue , Liu Lin , Lan Guoyu , Zhu Yalin , Chen Xuhui , Guo Lizhi , Zhou Yajing , Sun Kun , Zhu Lin , Kung Hank F. , Wang Qingyong , Xu Linsen , Han Ying , Wang Xinlu , Guo Tengfei
Published: December 2023

Background

N‐methylderivative of Amyvid (18F‐D3FSP) displayed very similar β‐amyloid (Aβ) targeting properties to the 18F‐florbetapir tracer, but it is not well established about the performance of 18F‐D3FSP Aβ positron emission tomography (PET) imaging in Alzheimer’s disease (AD).

Method

In this study, we recruited 142 Greater‐Bay‐Area Healthy Aging Brain Study (GHABS) participants from the community and completed Simoa plasma biomarkers, MRI imaging, 18F‐D3FSP Aβ PET imaging, and cognitive assessments. MRI images were segmented using FreeSurfer (v7.2.0) according to the Desikan–Killiany atlas. 18F‐D3FSP Aβ PET images were coregistered with their corresponding MRI scans, and intensity‐normalized to the mean uptakes in the whole cerebellum, cerebellar gray matter (cerebellar GM), brain stem (PONs), white matter, and big reference separately (Figure 1A). A cortical summary COMPOSITE 18F‐D3FSP standardized uptake value ratio (SUVR) in AD typical cortical regions was calculated. We used Gaussian Mixture Model to estimate 2 gaussian distributions of low and high Aβ for COMPOSITE SUVRs, and the threshold was defined as an SUVR corresponding to a 90% probability of belonging to the low‐Aβ distribution. COMPOSITE SUVRs were compared between Aβ‐ and Aβ+ groups. Finally, we investigated the association of COMPOSITE SUVR with plasma biomarkers, including age and sex as covariates.

Result

18F‐D3FSP Aβ PET imaging was capable of detecting fibrillary Aβ plaques in AD, and the Aβ+ group showed substantial Aβ deposition compared to the Aβ‐ group (Fig.1B). The dementia patients had more Aβ burden than the CU, SCD, and MCI individuals (Fig.1C), and the preclinical AD individuals (Aβ+/CU) showed significantly higher Aβ SUVRs than the Aβ‐/CI and Aβ‐/CU groups (Fig.1D). The comparisons of COMPOSITE SUVR between Aβ‐ and Aβ+ had a very high effect size, particularly in the brain stem reference region (Fig.2). Higher COMPOSITE SUVRs were related to lower plasma Aβ42/40 and higher plasma p‐Tau, GFAP, NfL concentrations, especially based on the composite big reference region (Fig.3).

Conclusion

[18F]D3FSP is an effective Aβ tracer to detect Aβ deposition in AD. Using the big reference may be optimal for calculating SUVR by considering the Aβ positive effect size and its correlation with Aβ, tau, neurodegeneration, and neuroinflammation measured in plasma.
Trajectories in Depressive Symptoms and Midlife Brain Health
Authors: Dintica Christina S. , Habes Mohamad , Erus Guray , Schreiner Pamela J. , Yaffe Kristine
Published: December 2023

Background

Evidence in older adults suggests that depressive symptoms may be part of prodromal mood changes in dementia, rather than a risk factor. However, it is unclear whether variations in depressive symptoms in adulthood exhibit distinct characteristics in brain structure and cognitive function in midlife.

Methods

From the Coronary Artery Risk Development in Young Adults study, we identified 662 Black and White participants (age 23‐36 at baseline) who completed the Center for Epidemiological Studies Depression scale (CES‐D) at six time points over 20 years. 20 years after baseline, the participants underwent magnetic resonance imaging to characterize gray matter (GM) structures (total GM, temporal cortex, hippocampus, and entorhinal cortex) and white matter hyperintensities (WMHs). Participants also completed neuropsychological tests including the Digit Symbol Substitution Test (DSST), Rey‐Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment (MoCA), and category and letter fluency tests, analyzed as z‐scores.

Results

Using growth mixture modeling, we identified four trajectories of depressive symptoms (Figure 1): consistently low scorers (“steady low”; n = 509, 76.9%), a class with an early peak and decline in symptoms (“declining”; n = 63, 9.5%), a class with late increases in symptoms (“increasing”; n = 49, 7.4%), and consistently high scorers (“steady high”; n = 41, 6.2%). Compared to the steady low class, the steady high class had lower entorhinal cortex volume (β: ‐180.80, 95% CI: ‐336.69 to ‐24.91). The increasing class, had more WMHs (β: 0.55, 95% CI: 0.22 to 0.89) and less total brain volume (β: ‐9269.25, 95% CI: ‐17104.67 to ‐1444.82). Both the steady high and the increasing classes had poorer performance on the Stroop task (β: ‐0.40, 95% CI: ‐0.70 to ‐0.10; β: ‐0.39, 95% CI: ‐0.64 to ‐0.14, respectively), however the steady high also had poorer DSST performance (β: ‐0.40, 95% CI: ‐0.67 to ‐0.13), while the increasing class had poorer performance on the MoCA (β: ‐1.20, 95% CI: ‐2.04 to ‐0.37). The declining group was not significantly different from the steady low group on any brain or cognitive measures.

Conclusions

Our findings suggest that trajectories in depressive symptoms in young to mid‐adulthood show different cognitive and brain phenotypes in midlife.
Prophylactic effect of passive immunotherapy with tau antibody 43D in 3xTg‐AD mice
Authors: Dai Chunling , Gong Cheng‐Xin , Iqbal Khalid
Published: December 2023

Background

Accumulation of abnormally hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Immunotherapy targeting tau represents a promising disease‐modifying therapeutic strategy for treating AD. We have found that immunization with monoclonal 43D antibody against tau 6‐18 weekly for 6 weeks can inhibit the seeding and spread of tau pathology templated by AD hyperphosphorylated tau, reduce both tau and Aβ pathologies and rescue cognitive impairment in 3xTg‐AD mice at mild to moderate stage of the disease. In this study, we investigated whether tau immunization with 43D prior to the onset of AD‐like pathologies can reduce AD‐like pathologies and improve cognitive function in 3xTg‐AD mice.

Methods

We immunized 3‐ to 4‐month‐old female 3×Tg‐AD mice with nine monthly doses of 15 µg of mouse monoclonal antibody 43D or, as a control, of mouse immunoglobulin G (IgG) intravenously. Age‐matched wild‐type mice treated with mouse IgG were also used as controls. The effect of immunization on cognition was analyzed by using one‐trial novel object recognition test and Morris water maze test, and the effect on tau pathology was assessed by Western blot.

Results

We found that 3xTg‐AD mice exhibited cognitive impairment as compared to the WT mice, as determined by novel object recognition test and Morris water maze test, and that immunization with 43D antibody improved the cognitive function seen in both tests. Immunization with 43D also decreased tau pathologies in the 3xTg‐AD mice. Additionally, long‐term treatment with 43D antibody did not display side events in 3xTg‐AD mice.

Conclusions

These findings suggest that passive immunization with 43D antibody targeting proximal N‐terminal domain tau 6‐18 may be as both prophylactic and therapeutic approaches for treating AD and related tauopathies.
Development of a web application for cognitive and functional assessment for dementia screening for Thai population
Authors: Senanarong Vorapun , Piyaamornpan Nattaporn , Srisuwannanukorn Suwat , Tangthamrongthanawat Kosit , Mekhasingharak Pornsawan , Rattanabannakit Chatchawan , Wongkom Natthamon , Hunnangkul Saowalak
Published: December 2023

Background

Tools for web‐based testing to detect cognitive impairment are still underdeveloped in Thailand. Our aim was to generate a web‐based instrument to assess cognitive and functional abilities and to explore its ability for diagnosis of dementia and MCI.

Method

We have developed a web application for cognitive and functional assessment to detect cognitive impairment. We hoped that subjects or family members could use this web‐based tests at home as self‐screening. These web‐based tests included an electronic version of the Thai Mental State Examination (e‐TMSE), a clock drawing test, a category verbal fluency test, a short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), and Thai activities of daily living scale (Thai ADL). Correlations, receiver operator curves (ROCs), sensitivity, and specificity were analyzed using SPSS (version 18).

Result

A total of 198 participants (69% female, mean age 66.7 ± 10 years). 57.1% had education of more than 6 years. Forty‐four were Major Neurocognitive Disorder, fifty‐eight were Mild Neurocognitive Disorder (MCI), and ninety‐six were normal controls. The e‐TMSE correlated with both paper‐pencil based TMSE(r = 0.80,p<0.001) as well as clock drawing test (r = 0.470 p<0.001). There were also statistically significant high correlations between digital and paper & pencil tests (e.g, category verbal fluency test, A short form of the IQCODE, and ADL). For diagnosis of dementia, e‐TMSE achieved an AUC of 0.84 (95% bootstrapped CI [0.78, 0.90]. The cut‐off score ≤23 offered sensitivity and specificity of 88.6% and 70.1% respectively. For diagnosis of dementia with the combination of 5 e‐tests, the AUC was 0.832 (p<0.001), while for MCI diagnosis, the AUC was 0.615 (p = 0.013). The area under the ROC of the IQCODE combined with ADL scale test was 0.907 (p<0.001).

Conclusion

We demonstrated that our web application that included: e‐TMSE, clock drawing test, category verbal fluency test, IQCODE and Thai‐ADL scale showed good correlation between digital vs paper‐pencil tests. Individual e‐test and combination of them can offer self screening for MCI and dementia.
A genome‐wide association study of LATE‐NC (limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change) reveals a distinct genetic architecture
Authors: Yang Hyun‐Sik , Mukherjee Shubhabrata , Latimer Caitlin S , Teng Ling , White Charles C , Yu Lei , Sperling Reisa A. , Larson Eric B , Crane Paul K , Keene C Dirk , Bennett David A. A , Schneider Julie A , De Jager Philip L
Published: December 2023

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is the third leading cause of late‐life dementia. However, its pathophysiology remains largely unknown, and the relationship of LATE‐NC with Alzheimer’s disease (AD) pathology and frontotemporal lobar degeneration‐TDP (FTLD‐TDP) remains unclear. To address this knowledge gap, we performed a genome‐wide association study (GWAS) of LATE‐NC.

Method

Deceased participants of European ancestry from the Religious Orders Study, the Rush Memory and Aging Project (ROSMAP, n = 1,379), and the Adult Changes in Thought study (ACT, n = 459) were included in our study. The primary phenotypes were LATE‐NC burden (a multi‐regional semi‐quantitative TDP‐43 composite, continuous) in ROSMAP, and the presence/absence of LATE‐NC (binary) in ACT, assessed with post‐mortem TDP‐43 immunohistochemistry. Quantitative amyloid‐β (Aβ) and paired helical filament tau (PHFtau) burden were also examined in ROSMAP. GWAS was performed using linear (ROSMAP) or logistic (ACT) additive models. We controlled age, sex, genotyping platforms, and the first three genotype principal components. Sample size‐weighted GWAS meta‐analysis (total n = 1,838) was performed by combining p‐values considering the direction of the association. Confounding and moderating effects of AD pathology on LATE‐NC risk variants were examined in ROSMAP.

Result

We observed two genome‐wide significant risk loci (p<5.0×10−8) in APOE (ε4) and SHANK2 (s146617441G, allele frequency 0.021). In ROSMAP, APOE ε4 was associated with higher LATE‐NC burden after controlling for quantitative Aβ and PHFtau (beta = 0.27, p = 7.3×10−6), and the APOE ε4 – LATE‐NC association was present in the subgroup without detectable Aβ (n = 170, beta = 0.50, p = 0.025). rs146617441G was not directly associated with quantitative Aβ or tau. Instead, rs146617441G×Aβ interaction term was associated with higher LATE‐NC burden (beta = 0.25, p = 0.032), suggesting the synergy between Aβ‐dependent and LATE‐NC‐specific pathways in LATE‐NC pathogenesis. Three additional loci reached a pre‐specified suggestive p‐value threshold (p<1.0×10−6; CMTM7 [rs56284874G], RNF145 [rs111653954T], and CACNA2D3 [rs71303704C]). A previously reported FTLD‐TDP risk locus in TMEM106B (rs1990622A) showed a weaker positive association with LATE‐NC (meta‐analysis p = 9.6×10−4).

Conclusion

Our GWAS revealed LATE‐NC‐specific risk loci (SHANK2 and other suggestive loci). The unique genetic architecture of LATE‐NC further supports the distinction between LATE‐NC and FTLD‐TDP, and the AD‐independent effect of APOE ε4 on LATE‐NC highlights the pleiotropic role of APOE in neurodegeneration.
“The place where danger waits”: Ten years of the 1994 Crime Bill incarceration on cognitive function in older adults racialized as Black
Authors: Adkins‐Jackson Paris AJ , Gobaud Ariana N , Kim Boeun , Higgins Cesar , Bailey Zinzi D , Hardeman Rachel R , Ford Tiffany N , Matz Meies‐Amor Blagburn , Uzzi Mudia , Gee Gilbert , Szanton Sarah L , Avila Justina F , Manly Jennifer J.
Published: December 2023

Background

Structural racism may drive the constellation of structural determinants that increase racialized disparities in the risk for Alzheimer’s disease related dementias (ADRD). Structural racism via adverse policing increases exposure to negative police encounters that produce heightened vigilance, anxiety, and depressed mood in persons racialized as Black. Seminal research suggests high‐police contact and disparities in Black‐White incarceration are positively associated with risk for other health conditions. It is feasible that cumulative stress from anticipatory and recurrent police encounters disrupts the body’s homeostasis leading to accelerated cognitive aging.

Method

We used US county‐level incarceration data to compute the Black‐White difference in prison and jail rates for US counties between 1995‐2005 (succeeding the 1994 Crime Bill). We then averaged the decade and linked said data by county to individual‐level health data for participants racialized as Black >50 years in the Health and Retirement Study (N = 2,300) who completed the core interview between 2006‐18 (mean observation of 3.4 per participant). Cognitive function was assessed using a 27‐item global cognitive score from the modified Telephone Interview for Cognitive Status. A mixed effects model was used to estimate the cognitive effect of a one‐unit change in incarceration (1,000 additional persons racialized as Black compared to White) with covariates of age at baseline, gender, education, and living arrangement.

Result

Greater Black‐White 10‐year difference in prison population was significantly associated with worse 2006 cognitive function (β ‐1.08, SE .45, 95% CI ‐1.96,‐.22). The adjusted model was significant for Black‐White difference in prison population with cognitive decline starting in 2006 (β .011, SE .006, 95% CI ‐.001, .023). The Black‐White difference in jail population was not significant.

Conclusion

Ten‐year Black‐White disparities in prison population are associated with cognitive decline among people racialized as Black starting one year later. While the 1994 Crime Bill is a decades‐old federal policy, it put into place a fiscal infrastructure which local governments continue to use to fund prisons, increase average prison time, and implement adverse policing quotas. These findings suggest structural racism via adverse policing is meaningful to explore in the context of ADRD.
Associations of objective and subjective neighborhood measures with cognitive change in a repeated measurement burst design
Authors: Hyun Jinshil , Katz Mindy J. , Derby Carol A. , Wang Cuiling , Lovasi Gina S , Sliwinski Martin J. , Lipton Richard B.
Published: December 2023

Background

Prior studies have reported associations between neighborhood characteristics and late‐life cognition. These studies assessed neighborhood using either objective (e.g., area‐level data from public database) or subjective (individual‐level perception) measures. However, little research has been done to examine effects of objective and subjective measures simultaneously. The present study aims to investigate the independent associations of objective and subjective neighborhood characteristics with cognitive change in older adults.

Method

Participants include 316 individuals in the Einstein Aging Study (mean age = 77; 67% females; 45% non‐Hispanic Whites, 40% non‐Hispanic Blacks). Subjective neighborhood measures included perceived neighborhood safety, aesthetic quality, social cohesion, and availability of healthy foods (range = 1 poor to 5 excellent). Objective neighborhood measures included violent crime, neighborhood deprivation, volunteering rates, percentage of healthy food retailers, and low access to healthy food. Processing speed was assessed using the brief, smartphone‐administered Symbol Search Test, and was completed 6x/day over two weeks; this was repeated annually from 2017 to 2022. To account for non‐linear retest/practice effects, double negative exponential models were used to estimate the relation of neighborhood measures to asymptotic performance (i.e., fastest response time) at baseline and to change in asymptotic performance over time.

Result

Most subjective and objective neighborhood measures were significantly correlated with each other (Table 1). In models containing both objective and subjective neighborhood measures, better perceived safety was associated with greater annual improvement in asymptotic performance (40 milliseconds/year for one point increase in safety) while the objective measure of violent crime was not. Perceived availability of healthy foods was independently associated with a faster baseline asymptotic processing speed (estimate = 160 milliseconds) and with greater annual improvement rate (estimate = 54 milliseconds/year) while the objective measures of food environment were not (Table 2).

Conclusion

Subjective rather than objective neighborhood characteristics were strongly associated with annual rates of change in processing speed over five years in community‐dwelling older adults. Perception of one’s neighborhood may be a more proximal predictor of cognitive health as it may reflect an individual’s lived experiences and determine one’s psychological states and health‐related behaviors. Alternatively, more fine‐grained objective neighborhood measures (e.g., individual‐level) would be necessary to better characterize objective neighborhood environments.
Plasma Alzheimer biomarker correlates of cerebrovascular disease in adults with Down syndrome
Authors: Edwards Natalie C. , Lao Patrick J. , Sedaghat Amirreza , Rizvi Batool , O'Bryant Sid E. , Mapstone Mark , Tudorascu Dana , Handen Benjamin L. , Christian Bradley T. , Wilcock Donna M. , Gutierrez Jose , Head Elizabeth , Brickman Adam M.
Published: December 2023

Background

By age 40 over 90% of adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology and most progress to dementia. Despite having fewer systemic vascular risk factors than neurotypical adults, recent studies demonstrate evidence of significant cerebrovascular disease in individuals with DS that track with the clinical progression of AD, suggesting a role for cerebrovascular disease that is not attributable solely to exposure to vascular risk factors. In the current study, we examined the codependency between white matter hyperintensity (WMH) volume, a marker of small vessel cerebrovascular disease, and AD pathophysiology, indexed with plasma AD biomarkers, in adults with DS.

Method

One hundred eighty‐seven participants from the Alzheimer Biomarkers Consortium – Down Syndrome (mean[SD] = 45.1[9.4] years) with available MRI and plasma biomarker data were included in the study. Whole‐brain WMH volumes were derived from T2‐weighted FLAIR MRI scans with in‐house software and plasma p‐tau217, Aβ42/Aβ40, and neurofilament light (NfL) concentrations were measured with SIMOA assays. Separate general linear models tested the association of WMH volume with each of the three biomarker concentrations; subsequent models were stratified by age, based on the median (46 years old).

Result

Higher WMH volume was associated with increased p‐tau217 and NfL concentrations but not with Aβ. In stratified analyses, the association between WMH and NfL concentration was stronger in younger adults than in older adults whereas the association between WMH and p‐tau217 concentration was stronger in older adults than in younger adults.

Conclusion

Our findings suggest a co‐dependency of cerebrovascular disease with tau pathology and neurodegeneration in adults with Down syndrome. Cerebrovascular disease may promote neurodegenerative changes in early adulthood and tau changes in later adulthood. The additional or alternative possibility that tau and neurodegeneration promote white matter changes cannot be ruled out in these cross sectional analyses. Future work will address the relative temporal emergence of these markers in adults with DS.
How are early career dementia researchers considered and supported by national dementia plans and dementia‐specific charities and associations? An overview of global policy approaches
Authors: Karamacoska Diana , Heins Pasclae , Branco Rita Maldonado , Wallcook Sarah , Truong Annie , Leung Isabella Hoi Kei , Sawan Mouna J , Page Zara A , Borelli Wyllians Vendramini , Arroyo‐Miranda Mirna L , Demnitz Naiara , Folarin Royhaan , Guo Tengfei , Shaaban C. Elizabeth , Smith Adam , Bartels Sara
Published: December 2023

Background

Early career dementia researchers (ECDRs) represent a crucial workforce to drive dementia research. Many charities, research leaders, and pressure groups, along with people living with dementia, continue to advocate for greater investment in dementia research. It remains unclear how ECDRs are being supported in this push for research through top‐down policy approaches. This study aimed to understand how ECDRs are considered and supported by national dementia plans or strategies across countries, and dementia‐specific charities and associations.

Method

Forty‐six countries from the G20 member states were evaluated. Each country’s dementia plan or strategy was reviewed alongside the policies of one governmental and one non‐governmental funding body. Data were gathered through internet searches and information requests to contacts at relevant organisations in each country. Data targeting support for ECDRs were extracted and subject to content analysis using inductive coding. Findings regarding ECDR support were categorised and narratively synthesised.

Result

Despite efforts to contact stakeholders directly, little to no information could be obtained from some countries due to language barriers. While most G20 member states have a national dementia plan or strategy, only China, the U.S. (excluding Puerto Rico), England, Scotland, Greece, and Denmark specifically mentioned ECDR support in their national policy, referring to creating specific ECDR funding and career opportunities. Thirteen countries were identified as providing targeted support for ECDRs via dementia‐specific charities or associations. This ECDR support reflected the following four categories: (1) research funding, such as fellowships and research grants; (2) research dissemination and networking, e.g., grants for printing a doctoral thesis or conference travel grants; (3) training and career development opportunities; and (4) research advice, including mentoring programs and grant writing assistance.

Conclusion

ECDR support varied greatly across the G20 member states, with few formally recognising ECDRs in their national dementia plan or strategy, and mixed support provided by dementia‐specific charities and associations or government bodies. Overall, ECDRs were not considered in dementia plans and strategies in the majority of included countries, and discrepancies between support levels exist across countries. To facilitate equal prospects for ECDRs, top‐down policy approaches are urged to enhance their efforts in the future.
Middle Age Prevention of Future Alzheimer’s Disease and Related Dementias with Intensive Treatment of Hypertension: Middle PATH Clinical Trial Proposal
Authors: Pruzin Jeremy J.
Published: December 2023

Strong epidemiological evidence from multiple studies suggests that elevated systolic blood pressure (SBP) in midlife is a risk factor for Alzheimer’s disease and Related Dementias (ADRD) later in life. The most common neuropathology of biomarker‐confirmed AD is combined AD neuropathological changes and cerebrovascular disease. Hypertension is a leading cause of cerebrovascular disease. The SPRINT MIND trial demonstrated that a goal SBP<120 mm Hg reduced risk for combined mild cognitive impairment (MCI) and dementia by 15% in older individuals compared to a goal SBP<140 mm Hg. SBP can be safely treated with inexpensive medications. Despite being potentially safe and cost‐effective, with strong supporting evidence for benefit, intensive SBP lowering in midlife to reduce future ADRD risk has never been studied, likely because clinical outcomes of MCI and dementia are not practical in this age range in a trial that is usually limited to about 5 years. Elevated SBP is a major risk factor for white matter hyperintensity volume (WMHV) accumulation, an MRI marker with extensive evidence demonstrating this to be associated with and predictive of incident ADRD, making WMHV a suitable surrogate outcome for the initial trial period. While we acknowledge the challenges of using a surrogate outcome, there is no suitable alternative when testing interventions to lower future ADRD risk starting in middle age, a strategy that we believe is essential. The Alzheimer’s Prevention Initiative and Wake Forest have formed a collaboration to investigate the effect of goal SBP<120 mm Hg compared to the SBP achieved by enhanced usual care (SBP≥135 mm Hg) on annualized rate of WMHV accumulation in persons ages 45‐65 who have some existing vascular risk at baseline. Secondary outcomes of changes in AD blood biomarkers and relevant cognitive test scores will help elucidate whether and how SBP and AD are interactive or independent deleterious pathophysiological processes. The intention, should the initial phase prove successful, is to continue and expand the trial until a clinical benefit can definitively be assessed.
The Brain Kidney Axis Vascular Cross Talk
Authors: Gupta Aditi
Published: December 2023

Chronic kidney disease (CKD) is associated with cognitive impairment and dementia; 87% of patients on chronic dialysis have some degree of cognitive impairment. The prevalence of CKD increases with age and approximately 40% of persons aged >60 years have CKD. With increasing life expectancy, prevalence of both CKD and dementia are expected to increase.

CKD and Alzheimer’s disease (AD) share common risk factors. Patients with CKD are older, and have multiple comorbidities such as hypertension, diabetes mellitus, dyslipidemia, metabolic syndrome, and obesity, making CKD a model for accelerated aging, inflammation, and vascular dysregulation. Inflammation and vascular dysregulation can disrupt blood brain barrier, decreased kidney function can influence amyloid clearance, an important AD biomarker. Patients with CKD have alterations in cerebral blood flow, brain white matter integrity, brain neurochemicals, and blood brain barrier permeability‐ findings that are similar to those seen in AD.

We investigated brain alterations seen in CKD before and after successful kidney transplant and found reversibility of brain alterations, and improvement in cognitive function after kidney transplantation. Further, we examined whether the cognitive impairment in CKD is due to comorbidities such as hypertension or due to decreased kidney function. In addition, for the first time, we have shown evidence for disruption of blood brain barrier in patients with CKD. With the high prevalence of CKD in the older population, and the strong association between decreased glomerular filtration rate and cognitive impairment, understanding the mechanisms underlying cognitive impairment and developing strategies to mitigate the risks in the CKD population is important.

The potential reversibility in brain alterations seen in CKD after a kidney transplant indicate an opportunity to develop strategies for management of cognitive impairment.
Tau epicenter identification and connectivity in clinically heterogeneous Alzheimer’s disease variants
Authors: Trainer Anne , Xu Wanwan , Chase Alison , O'Dell Ryan S. , Tun Samantha M , Li Joyce S , Ju Suyeon , van Dyck Christopher H , Mecca Adam P , Fredricks Carolyn
Published: December 2023

Background

While the spread of tau throughout the brain is well‐characterized in amnestic Alzheimer’s disease (AD), tau staging remains less clear for those suffering from clinically heterogeneous variants including logopenic variant primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA). We created a method to identify local maxima of tau SUVR (“epicenters”) in participants with early‐stage clinically heterogeneous AD with the goal of classifying participant subtypes based on the functional connectivity of these epicenters.

Method

We obtained 18F‐MK‐6240 tau PET scans from 10 participants with diagnoses of early‐stage clinically heterogeneous AD (5 lvPPA, 5 PCA, Clinical Dementia Rating 0.5‐1.0). We identified three local maxima of tau SUVR with a minimum specified distance of 20mm between them for each participant (Fig. 1). We then derived each epicenter’s functional connectivity in 1000 healthy controls using Neurosynth and sorted participants into subtypes based on the overlap of these functional connectivity maps.

Result

Participants with lvPPA showed highest tau burden in the posterior temporoparietal and temporoocciptal regions, left side predominant, and participants with PCA displayed highest tau burden in the bilateral parietooccipital cortex, frontal eye fields, and fusiform gyrus. We identified nine distinct subtypes of functional connectivity and most participants’ epicenters participated in more than one subtype. All subtypes highlight functional connectivity networks that have been associated with language and, or visuospatial processing. The most common subtype (seen in 7 of the 10 participants and 11 of the 30 epicenters) features connectivity within the bilateral occipital lobule, fusiform gyrus, and superior parietal lobule (Fig. 2).

Conclusion

We used a novel method to identify tau “epicenters” in the brains of participants with early‐stage clinically heterogeneous AD. Using these epicenters, we derived functional connectivity maps, which we then grouped into nine subtypes across participants. We will shortly begin collecting longitudinal tau PET in these clinically heterogeneous individuals with AD, allowing us to assess the extent to which tau spreads along the functional connectivity maps predicted by each participant’s epicenters and whether individually tailored epicenters outperform subtype classification. This work could serve as the basis for patient‐specific biomarkers of expected disease spread in clinically heterogeneous AD.
Investigating the effects of aerobic exercise primed anodal transcranial direct current stimulation on γ‐aminobutyric acid concentrations in mild vascular cognitive impairment
Authors: Wong Melissa , Near Jamie , Tumati Shankar , Gaur Amish , Siddiqui Mehreen , Gallagher Damien , Oh Paul I. , Marzolini Susan , Black Sandra E. , Swardfager Walter , Graham Simon J. , Ramirez Joel , Andreazza Ana C. , Rapoport Mark J. , Marotta Giovanni , Herrmann Nathan , Goubran Maged , Rajji Tarek K. , Lanctôt Krista L.
Published: December 2023

Background

Mild vascular cognitive impairment (mVCI) is characterized by minor deficits in cognition and memory due to underlying vascular pathology. Anodal transcranial direct current stimulation (atDCS), a non‐invasive neuromodulation technique, has been demonstrated to improve cognition. The effects of atDCS have been suggested to be mediated by γ‐aminobutyric acid (GABA)–a major inhibitory neurotransmitter associated with cerebral perfusion and oxygenation, and cognition and memory. However, previous studies have reported mixed results regarding changes in GABA concentrations following atDCS. Physical activity has been reported to increase cortical GABA levels, and in particular, aerobic exercise (AE) is associated with improved cognition in older adults. Preliminary data from an ongoing trial (EXPRESS‐V) was used to evaluate whether GABA concentration in the motor cortex was altered following AE and/or atDCS and whether this was associated with changes in global cognition in mVCI.

Method

In this double‐blind, randomized clinical trial, participants received one of four interventions for two weeks: AE and atDCS, AE and sham atDCS, exercise education and atDCS, or exercise education and sham atDCS. mVCI was determined based on a modified Gorelick criteria. At baseline and endpoint, GABA concentration in the motor cortex was measured using magnetic resonance spectroscopy and quantified with the Mescher‐Garwood point resolved spectroscopy pulse sequence, and global cognition was assessed using the Montreal Cognitive Assessment. Wilcoxon signed rank test was used to determine changes in GABA concentrations (ΔGABA). Spearman correlation was used to determine the association between ΔGABA and changes in global cognition (ΔMoCA).

Result

Ten participants have enrolled so far, with nine participants having completed the study (22.2% female, age = 66.4(9.8), years of education = 8.8(3.4), 55.6% White, baseline MoCA score = 22.8(3.1)). To date, ΔGABA was insignificant between baseline and endpoint (Z = 23.0, p = 0.953). However, a positive trend between ΔGABA and ΔMoCA was observed (ρ = 0.650, p = 0.058).

Conclusion

Preliminary results from nine participants showed a positive trend between ΔGABA and ΔMoCA. Since the trial is ongoing, with the target of recruiting 80 participants by 2024, analyses on unblinded data upon study completion will determine whether AE and atDCS leads to greater ΔGABA, and whether this is accompanied by greater ΔMoCA in mVCI.
Autophagy dysregulation in human fibroblasts from Niemann‐Pick type C patients
Authors: Pradel‐Bernal Tamara Patricia , Alcala‐Flores Rebeca‐Leticia , Gomez‐Virgilio Laura , Silva‐Lucero Maria‐del‐Carmen , Rivera‐Osorio Jared , Cardenas‐Aguayo Maria‐del‐Carmen
Published: December 2023

Background

Niemann‐Pick disease type C (NPC) results from a mutation in the gene that encodes endolysosomal cholesterol‐transport proteins NPC1. NPC is characterized by the accumulation of unesterified cholesterol and other lipids within the cell causing the impaired function of lysosomes and the autophagy flux. The symptoms of the disease are variable and may include: enlarged liver or/and spleen, learning difficulties, seizures, gait problems, dementia, and loss of muscle tone, among others. Macroautophagy is the main recycling pathway of organelles and cellular components in mammalian cells to obtain primary elements in stress conditions such as the absence of nutrients and maintaining cellular homeostasis. During disease, it also helps to get rid of toxic misfolding protein aggregates. Many neurodegenerative diseases are characterized by autophagy impairment.

Method

In this study, we worked with 3 skin fibroblast cells lines from apparently healthy subjects and 3 from Niemann‐Pick’s patients to corroborate altered autophagy flux made an autophagy induction by chloroquine (10 uM) and serum starvation, first we performed the Cyto‐ID autophagy (Enzo) detection kit and then we analyzed by Western blotting the expression of proteins that are involved in the autophagy pathway to find the altered mechanisms.

Result

Chloroquine treatment induced a significant decrease in the viability of NPC cells as compared to controls, which correlates with an increase in cytoplasmic autophagy vacuoles (Avs) and an increase in LC3‐II. Also, there was an increased trend in LC3‐II, ATG5, ATG16‐L1 in NPC cells cultured in the presence and absence of nutrients. No significant changes were observed in the expression of p62 between NPCs and control cells.

Conclusion

NPCs are more sensitive to autophagy induction by Chloroquine than control cells, as demonstrated by morphology (increase in AVs) and LC3‐II, ATG5 and ATG16L1 expression, detected by Western blotting.