bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain extracellular vesicles from Alzheimer’s Disease and Down Syndrome patients mediate spread of senescence‐like phenotype in vitro
Authors: Bilousova Tina , Melnik Mikhail , Matsuo Yuriko , Kodavatikanti Achyutha , Knitowski Nina , Atluri Swetha , Gylys Karen H
Published: December 2023

Background

Alzheimer’s disease (AD) is the prevalent cause of dementia in older adults. Down Syndrome (DS) is the most common chromosomal disorder with strong predisposition to the development of AD. Cellular senescence contributes in the pathophysiology of both AD and DS but the mechanisms are unclear. Senescence associated secretory phenotype (SASP), which refers to a complex of secreted mediators, including soluble factors and extracellular vesicles (EVs) may contribute to the spread of senescence to bystander cells but its role in neurodegenerative disorders has not been evaluated.

Method

Parietal cortex tissue from patients with AD, DS, and normal/low‐pathology (NL) cases was obtained from the UC Irvine ADRC. The cryopreserved human tissue was used for small EV isolation by ultracentrifugation and size exclusive chromatography (SEC). Purity of the EV fractions was confirmed by immunoblotting against positive (CD63, CD9, Syntenin‐1) and negative (calnexin and GM130) EV/exosomal markers, transmission electron microscopy, and nanoparticle tracking analysis. Cell‐type specific EV fractions were isolated by immunoprecipitation (IP). Senescence transfer potential of brain‐derived EVs were assessed in neuroblastoma and glioma cells using senescence associate beta‐galactosidase activity assay, and confirmed by other senescence markers.

Result

Our preliminary data demonstrated the ability of AD and DS, but not NL samples, to transfer senescence to neuroblastoma SH‐SY5Y and glioma U87‐MG cells. Senescence associate beta‐galactosidase activity was on average around 15% higher in cells treated with AD brain derived EVs (AD‐EVs) compared to NL brain EVs (NL‐EVs). This data correlates with around 20% elevation in p21 expression in AD‐EV treated cells. When senescence transfer potentials were compared between AD‐EVs and DS brain derived EVs (DS‐EVs), DS‐EVs exceeded AD‐EVs in their ability to transfer senescence‐like phenotype with around 40% increase in senescence associate beta‐galactosidase activity in cells treated with DS‐EVs. We are currently evaluating levels of senescence‐associated and SASP markers in AD and DS cells and cell‐type specific brain derived small EVs.

Conclusion

We demonstrated an ability of AD and DS brain derived EVs to transfer senescence‐like phenotype in vitro. This phenomenon deserves further investigation to estimate its impact on the progression of AD in Down and non‐Down population along with evaluation its therapeutic potential.
Relationship between psychiatric symptoms and bidirectional change in subjective cognitive decline
Authors: Kann Michael , Chapman Silvia , Joyce Jillian L. , Waltrip Leah H. , Zeiger Peter , Rizer Sandra , Shagalow Shaina , Azar Martina , Cosentino Stephanie
Published: December 2023

Background

Subjective Cognitive Decline (SCD) is increasingly recognized as a prodromal risk state for Alzheimer’s disease. However, relatively little is known about trajectories of SCD within cognitively normal older adults, or the factors that associate with SCD change in this group. In this study, we examine the extent to which specific psychiatric symptoms including anxiety, depression, and apathy associate with an individual’s change in SCD over time.

Method

Participants were community dwelling cognitively normal older adults. SCD was measured using a 20‐item age‐anchored questionnaire that assessed complaints of cognitive functioning. Anxiety, depression, and apathy were assessed using the Beck Anxiety Inventory(BAI), Geriatric Depression Scale(GDS), and Apathy Evaluation Scale(AES), respectively. Measurements were conducted at two timepoints (T1 and T2). Average duration between visits was 35.62 months(SD = 13.28). High SCD change individuals(HC), as opposed to low SCD change individuals(LC), were defined as those who’s total SCD rating changed more than ±1 SD from the mean change score. Regression models were conducted to examine the association between SCD change group and psychiatric symptoms.

Result

Participants were 82 cognitively normal older adults (6.1% Hispanic, 93.9% Non‐Hispanic; 79.3% White, 15.9% Black; 67% female; mean age = 70.96(SD = 6.98); mean education = 16.38(SD = 2.26)). 22 participants were classified as HC(11 with increasing SCD; 11 with decreasing SCD). Anxiety symptoms were higher in the HC group than the LC group at T1(6.57 vs 3.53, p = 0.013) and T2(6.70 vs 2.91, p = 0.003). After adjusting for demographics(age, gender, and education), only T1 anxiety was associated with the HC group(B = 0.297, p = 0.017).

Conclusion

Individuals with greater change in SCD over time had higher levels of anxiety at baseline than individuals with relatively stable SCD. This was true for individuals who had a large increase in SCD as well as a large decrease. Our results inform the factors that may contribute to variability in SCD among cognitively normal older adults and underscore the importance of assessing anxiety along with SCD. Importantly, as psychiatric symptoms may also confer risk for future dementia, current findings do not undercut the potential relevance of SCD for future cognitive decline and dementia. Ongoing longitudinal research is examining the interplay of SCD change, psychiatric symptoms, objective cognition, and diagnostic conversion.
Impact on End‐of‐life Planning of a Care Coordination Program for persons living with dementia
Authors: Tan Zaldy S. , Qureshi Nabeel , Kremen Sarah , Rhinehart Deana , Gatmaitan Dyane , Spivack Erica , Guinto Augustine , Sicotte Nancy
Published: December 2023

Background

Alzheimer’s disease and related dementias (ADRD) afflict over five million persons in the U.S., and persons living with dementia (PLWD) have been shown to receive poor quality care and have worse health outcomes compared to those without ADRD. We developed a population‐based dementia care management program to support the care of PWLD in a large U.S. healthcare system.

Methods

In a large multi‐specialty medical group practice, we identified patients enrolled in a value‐based insurance program (Medicare Advantage) using the EPIC electronic health record (EHR), and eligible patients were invited to enroll in the CARES dementia care program. Patients were eligible if they had an ICD‐10 diagnosis of ADRD in the EHR problem list and/or past medical history, or currently taking an FDA‐approved medication for ADRD. We additionally included patients with ADRD who have a primary care provider in the affiliated academic health system. During an in‐person intake visit, a study‐assigned nurse practitioner (NP) engaged in advance care planning discussion with patients and caregivers and completed advance directives (AD) and Physician Order for Life Sustaining Treatment (POLST). We assessed the rate of completion of the AD and POLST pre‐program and post‐enrollment.

Results

We enrolled 195 patients in the CARES dementia care program. After enrollment, participants increased completion of advanced directives from 27.7% to 30.8% (p = 0.25) and the POLST from 13.3% to 23.1% (p = 0.006). Of the POLST forms completed, 70.7% indicated that the patient was ‘do not attempt resuscitation’ (DNAR) (65.2% of those who completed the POLST pre‐program, 77.8% for those who completed after enrollment, p = 0.19). Among those who completed the POLST, 55.0% indicated selective medical interventions (63.6% pre‐program, 47.1% post‐enrollment, p = 0.15), 40.0% wanted full medical interventions (31.8% pre‐program, 52.9% post‐enrollment, p = 0.10), and 5.0% wanted comfort‐focused interventions (4.5% pre‐program, 5.9% post‐enrollment, p = 0.43). Trial period of nutritional supports was indicated by 69.2% (72.7% pre‐program, 64.7% post‐enrollment, p = 0.28), while 28.2% wanted no artificial treatment (27.2% pre‐program, 29.4% post‐enrollment, p = 0.45), and 2.6% wanted long‐term nutritional support (0% pre‐program, 5.9% post‐enrollment, p = 0.13).

Conclusion

A dementia care coordination program shows signs of increased completion of end‐of‐life planning, with the majority choosing ‘do not attempt resuscitation’ (DNAR).
Validated, unified theory of Alzheimer Disease illuminates two essential research questions
Authors: Kennedy Alison Ruth
Published: December 2023

Background

A 2001 unified theory of thiamine deficiency (TD) in Alzheimer Disease (AD) (1‐p.85) was validated in 2015 (2), and published in 2017 (3). Update?

Method

Scientific literature review on topic of thiamine and/or AD. PUBMED, elibrary.wiley.com, mspace.lib.umanitoba.ca

Result

1. Thiamine supplementation can potentially correct key AD abnormalities: the cholinergic deficit (1‐p.64, 4), B‐Amyloid (1‐p. 77, 3), tau (5), neuroinflammation (4, 5,6, 7) and memory (1‐p59).

2. Limited oral thiamine supplementation trials in AD have had mixed results (1‐p49, 6).

Conclusion

Essential research questions:

a. What causes TD in AD? (altered thiamine requirements, excretion, absorption, transport, metabolism, or diet and other factors*?) (1)

b. What is the optimal treatment of TD in AD? (control for medications*, medical conditions* and dietary components affecting thiamine intake and utilization* (1‐p. 52, 1‐p.53,9). Consider advantages of intramuscular injections vs. oral treatments (8), need for other nutrients (1‐p.52), proven thiamine treatments in TD diseases.

References:

1. Kennedy, A.R. (2001). The potential role of thiamine in the pathogenesis and treatment of Alzheimer’s Disease. M.Sc. dissertation. University of Manitoba, Winnipeg. http://mspace.lib.umanitoba.ca/handle/1993/19635

2. Pan, X. (2015). Measurement of brain thiamine metabolites for Alzheimer Disease diagnosis. 2015 Nov 26. doi: 1016/j.ebiom.2015.11.039

3. Kennedy, A.R. (2017). Scientific evidence supporting a unified theory of Alzheimer Disease. Alzheimers Dement,13(7S)_ Part_31/p.P1478‐P1478 https://doi.org/10.1016/j.jalz.2017.07.551

4. Lu’o’ng, K., Nguyen, LT (2011). Role of thiamine in Alzheimer’s Disease. Am J Alzheimer’s Dis Other Demen., 26(8):588‐598. https://doi.org/10.1177/1533317511432736

5. Tapias, V. et al. (2018). Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of taupathy. Hum Mol Genet Aug 15; 27(16): 2874‐2892. https://doi.org.10.1093/hmg/ddy201

6. Fessell, J. (2021). Supplemental thiamine as a practical, potential way to prevent Alzheimer’s disease from commencing. Alzheimers Dement: Translational Research and Clinical Interventions. 7 (1)/e12199. https://doi.org/10.1002/trc2.12199

7. Sambon, M. et al. (2021). Neuroprotective effects of thiamine and precursors with higher bioavailability: Focus on benfotiamine and dibenzoylthiamine. Int. J. Mol. Sci. 22(11):5418. https://doi.org/10.3390/ijms22115418

8. Baker, H., et al. (1980). Oral versus intramuscular vitamin supplementation for hypovitaminosis in the elderly. J Am Geriatr Soc., 28(1):42‐45. https://doi.org/10.1111/j.1532-5415.1980.tb00123.x.

9. Vora, B. et al. (2020). Drug‐nutrient interactions; discovering prescription drug inhibitors of the thiamine transporter ThTF‐2 (SLC19A3). Am J Clin Nutr., 111(1), 110‐121. https://doi.org/10.1093/ajcn/nqr255
TMS and imaging correlates of spasticity in persons at‐risk for the A431E PSEN1 mutation
Authors: Iyer Pooja , Shi Yonggang , Ringman John M
Published: December 2023

Background

Spastic paraparesis (SP) occurs in approximately 45% of carriers of the A431E PSEN1 mutation (MCs), sometimes preceding cognitive decline. SP is typically caused by reduced cortical excitatory output to spinal motor neurons resulting from delayed cortical conduction time or increased inhibitory output from cortex. Previous studies have observed that people with spasticity have increased corticospinal inhibition at rest and altered interhemispheric inhibitory control (amount of inhibition and conduction time) during isometric contraction. Hence, in this study, we sought to identify transcranial magnetic stimulation (TMS) and diffusion MRI and flortaucipir PET imaging predictors of SP using these inhibitory measures captured using TMS.

Method

We included 19 persons known to be at‐risk for the A431E PSEN1 mutation (15 MCs, 3 NCs) and one person affected by the F388S PSEN1 mutation who participated in a comprehensive study of autosomal dominant AD including TMS, diffusion MRI, and flortaucipir PET. We measured cosrticospinal inhibition for lower limbs at rest by targeting tibialis anterior muscle representation at primary motor cortex. For inter‐hemispheric inhbition (extent of inhibition and transcallosal conduction time), we stimulated the hemisphere ipsilateral to the limb performing isometric contraction. We ran a non‐parametric regression model for prediction using the gsm function from the npreg package in R© because several variables were not normally distributed (Shapiro‐Wilk test, p<0.05).

Result

Spasticity score (Ashworth scale) was positively associated with interhemispheric inhibition, transcallosal conduction time, and DTI measures of the corticospinal tract and pre‐post‐para central lobes of both hemispheres (Spearman rank correlation, p< 0.05). Among all inhibitory TMS measures and DTI variables, the transcallosal conduction time for the lower limbs (β = 2.87) and suvr_rh_paracentral (β = ‐25.92) independently predicted increased spasticity scores. The interaction effect between these measures was insignificant. The prediction model had an adjusted R2 value of 0.89.

Conclusion

We show increased transcallosal conduction time and decreased white matter integrity around the right‐hemisphere paracentral lobule is associated with increased mean spasticity scores in people with A431E PSEN1 mutations. This is consistent with other studies showing altered interhemispheric control in SP. Delay in transcallosal conduction time in A431E PSEN1 MCs may compromise inter‐hemispheric control limiting smooth movement control.
The relation between adverse childhood experiences and fostering health behaviors in adult women
Authors: Tsotsoros Cindy E , Tavares Karina L.
Published: December 2023

Background

Adversity in early childhood plays a central role in health outcomes later in life. Social determinants of health, such as environment, play a role in lifestyle habits developed and possessed throughout adulthood. The more adverse childhood experiences (ACEs) an individual has, the more likely they are to have negative physical and mental health outcomes (Sacks & Murphey, 2018).

Method

Data was collected in a larger cohort study assessing biomarkers in women between the age of 65‐85. Among the 232 women, two groups were recruited: individuals with 0 ACEs and individuals with 3 or more ACEs. Survey data was collected from participants and analyzed using SPSS Version 28. Health lifestyle was measured using the Health‐Promoting Lifestyle Profile (HPLP‐II; Walker, et al., 1987). The HPLP‐II has six subscales: health responsibility, nutrition, spiritual growth, physical activity, stress management, and interpersonal relations. ACEs were measured with the Adverse Childhood Experiences Questionnaire (Felitti et al., 1998) and addressed three categories of adversity: abuse, neglect, and household dysfunction (HD).

Result

The 87 participants who had zero ACEs (M = 2.56, SD = 0.46) compared to the 145 participants with three or more ACEs (M = 2.18, SD = 0.41) demonstrated significantly higher HPLP‐II scores indicating that healthier behaviors are performed more frequently for those with zero ACEs, t(230) = 6.65, p<.001. All of the multiple linear regressions were overall statistically significant (HPLP‐II (R2 = .17, F(3, 228) = 16.44, p<.001); health responsibility (R2 = .07, p< 001); physical activity (R2 = .05, p = .002); nutrition (R2 = .07, p<.001); spiritual growth (R2 = .17, p<.001); interpersonal relationships (R2 = .13, p<.001); stress management (R2 = .12, p<.001)). Neglect and HD significantly predicted overall HPLP‐II ((β = ‐.21, p = .012); (β = ‐.19, p = .008)) and interpersonal relationships ((β = ‐.23, p = .008); (β = ‐.23, p = .003)). HD significantly predicted health responsibility (β = ‐.18, p = .022) and nutrition (β = ‐.22, p = .005). Neglect significantly predicted spiritual growth (β = ‐.25, p = .003). Abuse significantly predicted stress management (β = ‐.17, p = .05), and was trending in predicting physical activity (β = ‐.16, p = .078).

Conclusion

ACEs play a significant role in future health behaviors, with household dysfunction being the largest predictor.
Plasma biomarker and neuroimaging changes in a Chinese community aging cohort: The Greater‐Bay‐Area Healthy Aging Brain Study (GHABS)
Authors: Guo Tengfei , Zhang Mingkai , Shi Dai , Li Yuxia , Chen Xuhui , Zhao Ruiyue , Lan Guoyu , Cai Yue , Sun Pan , Li Anqi , Zhu Yalin , Liu Lin , Guo Lizhi , Zhou Yajing , Liu Zhen , Sun Kun , Wang Xinlu , Xu Linsen , Wang Qingyong , Han Ying
Published: December 2023

Background

To investigate the alternations of β‐amyloid (Aβ), tau, neurodegeneration, and cognition in different stages of Alzheimer’s disease (AD) in the Chinese community aging population is important for early diagnosis and intervention of AD in China.

Method

We recruited 422 Greater‐Bay‐Area Healthy Aging Brain Study (GHABS) participants from the community and completed cognitive assessments, including 100 cognitively unimpaired (CU), 189 subjective cognitive decline (SCD), 82 mild cognitive impairment (MCI) and 51 AD dementia individuals. Among them, 343 individuals had plasma Aβ42/Aβ40, p‐Tau181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) data measured by the Simoa platform. Furthermore, 159 and 96 individuals had concurrent MRI and 18F‐D3‐FSP Aβ PET scans, respectively. Generalized linear models were used to compare plasma biomarkers, AD typical cortical FSP Aβ standard uptake value ratio (SUVR), residual hippocampal volume (rHCV), and cognitive scores between different clinical and A/T (A: plasma Aβ42/Aβ40, T: plasma p‐Tau181) groups, controlling for age and sex. Multiple comparison corrections were conducted (Benjamini‐Hochberg, p<0.05). The association of plasma Aβ42/Aβ40 and p‐Tau181 with plasma NfL, GFAP, Aβ PET, rHCV, MoCa, and SCD‐Q were also investigated, including age, sex, and diagnosis as the covariates.

Result

SCD individuals had higher plasma p‐Tau181 (standardized β (βstd) = 0.251[95% confidence interval (ci): 0.031, 0.472], p = 0.038) and GFAP (βstd = 0.259[95% ci: 0.035, 0.483], p = 0.023) than the CU individuals (Figure 1). Compared to the A‐/T‐ group, A+/T+ individuals had more (p<0.001) abnormal changes in all the plasma biomarkers, Aβ PET, rHCV, and MoCa, and A‐/T+ individuals had more hippocampal atrophy (p = 0.012) and marginal higher plasma NfL (p = 0.074) (Figure 2). Continuously, lower plasma Aβ42/Aβ40 was only related to higher plasma GFAP (p<0.001), whereas plasma p‐Tau181showed significant association with plasma NfL (p<0.001), plasma GFAP (p = 0.026), Aβ PET (p = 0.028), and MoCA (p = 0.023) (Figure 3).

Conclusion

This study summarizes the characteristics of plasma biomarkers and brain imaging of AD and provides novel insights into the alternations of Aβ, tau, neurodegeneration, neuroinflammation, and cognition in different stages of AD in Southern China’s aging population. These findings are critical for using plasma biomarkers and neuroimaging to detect early AD changes in China.
The AβpE 3‐42 peptide is associated with a higher degree of inflammation than Aβ1‐40 in brains with Alzheimer’s disease.
Authors: Soto‐Rojas Luis Oskar , Harrington Charles R , Carmen Cardenas‐Aguayo Maria , Cruz‐López Fidel , Viramontes‐Pintos Amparo , Gevorkian Goar , Luna‐Muñoz José
Published: December 2023

Background

Alzheimer’s Disease (AD) is the most common neurodegenerative disease histopathologically characterized by the presence of neuritic plaques (NPs), extracellular deposits composed of amyloid beta peptide (Aβ) and neurofibrillary tangles (NFTs) composed of tau protein. It has been hypothesized that Aβ promotes synthesis and secretes proinflammatory proteins causing neuronal and endothelial damage in the AD brain. In this context, it is not clear if the truncated Aβ species can be more toxic than the full‐length ones. Therefore, this work aimed to explore the association of the Aβ1‐40 peptide (full length) and AβpE3‐42 (truncated species) with inflammation in the brains of AD patients.

Method

We used postmortem tissue from the temporal cortex of patients with AD and it was analyzed by confocal microscopy using antibodies against the peptide Aβ 1‐40 and AβpE 3‐42, phospho tau and caspase‐5 (inflammatory type caspase). The amyloidogenic plaques AB1‐40 and AβpE3‐42 and their association with the inflammation marker caspase 5 were quantified. In addition, caspase 5 was quantified by western blot (WB) in control brains and those with AD.

Result

We found high caspase‐5 immunoreactivity specifically associated with extracellular Aβ peptide deposits. Interestingly, this caspase 5 is associated preferentially with the truncated Aβ pE 3‐42 peptide. Likewise, caspase‐5 was expressed mainly in brain blood vessels which had Aβ peptide deposits. We did not detect the colocalization of this enzyme with the tau protein. WB assays show increased caspase 5 in AD brains compared to controls.

Conclusion

In conclusion, our findings show that the truncated AβpE3‐42 peptide is closely associated with caspase 5, a key enzyme in the inflammation process. This latter may be a specific biomarker of inflammation in AD brains.
Predictive analysis between cytokine profile and Aβ42, p‐Tau, and p‐Tau/Aβ42 levels in the cerebrospinal fluid of older adults with and without cognitive impairment
Authors: Bolaños Burgos Ivonne Carolina , Aquino Pedro Henrique Oliveira , Ribeiro Julia Mendes , de Andrade Rafael Souza , Engelmann Gabriela Tomé Oliveira , Hansen Erika de Oliveira , Dias Natália Silva , Carvalho Andréa Teixeira , Miranda Debora , Romano‐Silva Marco Aurelo , de Marco Luiz Armando Cunha , Viana Bernardo de Mattos , Bicalho Maria Aparecida Camargos
Published: December 2023

Background

The immune system activation observed in Alzheimer’s disease (AD) pathology contributes to its pathogenesis. It is proposed that ongoing interactions between β‐amyloid plaques, Tau protein, and neuroinflammatory mediators such as cytokines contribute to the maintenance of the inflammatory state in the brain. The aim was to evaluate whether cytokine profiles can predict variations in Aβ42, pTau, and pTau/Aβ42 cerebrospinal fluid (CSF) levels in older adults with and without objective cognitive impairment.

Methods

Eighty older adults were recruited, with a clinical diagnosis of AD dementia (36), with Mild Cognitive Impairment (MCI) (24), and without objective cognitive impairment (20). CSF levels of Aβ42, pTau, and 27 cytokines were assessed by the Luminex xMAP technique. Significant associations between Aβ42, p‐Tau, and p‐Tau/Aβ42 CSF levels and cytokines were explored in multiple linear regression analyses adjusted for age, education, and APOE ε4 carrier status.

Results

We found that Granulocyte and Macrophage colony‐stimulating factors (GM‐CSF) (β = ‐.375; p = .010) and IL‐6 (β = ‐.370; p = .014) had a negative significant association with Aβ42, while IL‐8 (β = .452; p = .002) and IL‐4 (β = .488; p = .001) had positive significant association and higher magnitude of effect on Aβ42. For pTau, age (β = .240; p = .029), IL‐2 (β = .314; p = .012) and ε4 allele (β = 0.349; p = .002) had a positive significant association. The variable with the greatest magnitude of the effect was the presence of the ε4 allele. For the p‐Tau/Aβ42 ratio, G‐CSF (β = .423; p = .003) and GM‐CSF (β = .317; p = .019) had a significant positive association, while for IL‐8 (β = ‐.554; p = .001) and IL‐12 (β = ‐.334; p = .019) the association was significantly negative. IL‐8 had the greatest magnitude of effect on p‐Tau/Aβ42 ratio values.

Conclusion

The higher levels of IL‐4 and the IL‐8 associated to a higher Aβ42 suggest their role at the beginning of the disease. On the other hand, the lower level of IL‐8 associated with a higher p‐Tau/Aβ42 suggests its inactivation as the disease progresses. Conversely, the higher levels of GM‐CSF associated with higher p‐Tau/Aβ42 suggests a more robust recruitment of the immune cell system at later stages.

Reference: Aksnes, M., et al., (2021). Associations of cerebrospinal fluid amyloidogenic nanoplaques with cytokines in Alzheimer’s disease. Translational Neurodegeneration.
A CenTauR scale based on 18F‐MK6240
Authors: Dore Vincent , Bourgeat Pierrick , Leuzy Antoine , Huang Kun , Krishnadas Natasha , Feizpour Azadeh , Fripp Jurgen , Villemagne Victor L , Rowe Christopher C
Published: December 2023

Background

A standardized scale for the quantification of tau PET imaging would allow comparison and combination of data across tracers and sites resulting in large meta‐analysis and the application of universal cut‐offs. The proposed approach called CenTauR (CTR) was evaluated on 18F‐MK6240 using both global and regional anchoring.

Method

375 18F‐MK6240 PET & T1w scan pairs (HC Aβ‐ = 179/MCI Aβ+ = 98/AD Aβ+ = 98) from AIBL&ADNeT were spatially normalised using SPM8 and SUVR normalised using the cerebellar cortex. PET scans were then quantified in 4 composite ROIs [Mesial‐Temporal (Me), Meta‐Temporal (MT), Temporo‐Parietal (TP) and Frontal (FT)] from a previously defined “universal” cortical mask. To anchor the 0 and 100 CTR, we only included HC Aβ‐ (<10CL) and AD Aβ+ (>25CL) individuals younger than 75y, with MMSE ≥20, we also excluded HC participants with a quantification higher than the 75%tile in the Me and AD patients with a quantification lower than the 25%tile in the MT, resulting in 68 HC Aβ‐ and 29 AD Aβ+. We investigated two CTR scaling approaches using either a single transform based on the TP anchors to transform SUVR into CTR for all composites or using region‐based equations scaled with regional anchors.

Result

The mean and standard deviation (std) for the HC and AD groups are reported in Table 1.

Using a single transformation resulted in the following equation

:

Ct = 100x(SUVR‐0.97)/2.26

Region‐based equations can be extrapolated from Table 1. Figures 1 and 2 show that regional CTR overstretches quantification in FT compared to single equation‐derived CTR. Thresholds set at 2 std above the HC were 2.38, 9.43, 7.66, 1.82, and 6.16 CTR for Me, MT, TP, FT and Global respectively, and were 7.05, 7.48, 7.66, 10.20, 7.68 CTR when using regional equation‐derived CTR.

Conclusion

The region‐based approach provided slightly more consistent CTR distributions in the HC across the ROIs however, this approach tends to over‐stretch the CTR values in the frontal region.
Comparison of plasma and cerebrospinal fluid protein markers and their significance for the characterization of dementia disease status
Authors: Rehman Habbiburr , Ang Ting Fang Alvin , Tao Qiushan , Zhang Xiaoling , Qiu Wei Qiao
Published: December 2023

Background

Although Aβ42 and phosphorylated tau (p‐tau) in cerebrospinal fluid (CSF) are valuable to diagnose Alzheimer’s disease (AD), many patients are reluctant to accept lumbar puncture. In addition, there is lack of biomarkers for the different stages of AD dementia. This study sought to compare the plasma and CSF protein markers to characterize dementia status.

Method

This cohort study included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 73 proteins measured in plasma (566 total, 58 cognitively normal (CN), 396 mild cognitive impairment (MCI), and 112 AD) and in CSF (310 total, 92 CN, 149 MCI, and 69 AD). Univariate/multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) were used to identify the protein candidates for the disease classification. The following three models were examined for CN vs. MCI and MCI vs. AD; model 1: proteins only, model 2: proteins adjusted for age, sex, education, and model 3: model 2 plus APOE4 status.

Result

Nine proteins in plasma and CSF were chosen based on their importance from LASSO. The area under the curve (AUC) for the final multivariate logistic regression including the 9 proteins was calculated for each disease group in plasma [CN vs. MCI: 0.895 (model 1), 0.899 (model 2), 0.921 (model 3), and MCI vs. AD: 0.828 (model 1), 0.842 (model 2), 0.856 (model 3)]. In addition, AUC in CSF [CN vs. MCI: 0.678 (model 1), 0.726 (model 2), 0.770 (model 3) and MCI vs. AD: 0.711 (model 1), 0.738 (model 2), 0.765 (model 3)] was also estimated. We observed that plasma proteins outperformed the CSF proteins to be associated with MCI and AD. Also, plasma proteins were significantly better than the established AD markers, namely CSF Aβ42 and p‐tau in CN vs. MCI [AUC: 0.836 (model 1), 0.842 (model 2), 0.862 (model 3)] and MCI vs. AD [AUC: 0.665 (model 1), 0.673 (model 2), 0.680 (model 3)].

Conclusion

This study demonstrates that the combination of plasma proteins could be considered an effective marker for diagnosing AD and its early‐stage symptoms with better performance than the other markers.
Neuropsychiatric co‐morbidities and psychotropic medication use in Medicare beneficiaries with dementia
Authors: Johnson Kim G , Ford Cassie , Clark Amy G , Greiner Melissa , Lusk Jay , Perry Cody , O'Brien Richard , O'Brien Emily C
Published: December 2023

Background

Neuropsychiatric symptoms affect approximately 97% of patients with dementia. Prevalence of symptoms may be different dependent upon age, sex or race. Past studies report high rates of potentially inappropriate prescribing in the dementia population. We investigate differences in neuropsychiatric diagnoses and psychotropic medication prescribing in a local US cohort.

Method

We utilize Medicare claims and Medicare Part D prescription fill records in a cohort of 100% Medicare North and South Carolina fee‐for‐service beneficiaries ages 50 and above for the year 2017 with a dementia diagnosis. We identify dementia based on an ICD‐10‐CM diagnosis of dementia from an inpatient, outpatient, carrier, skilled nursing facility or home health claim, or a prescription claim for drug treatment between 1/1/2017 and 12/31/2017. We quantified neuropsychiatric diagnosis of anxiety, depression and psychosis using validated coding algorithms, searching inpatient, outpatient and physician 2017 claims. Demographic characteristics, including age, sex and race, as well as dual Medicare/Medicaid status were collected from the MSBF file for each individual. We search generic medication names in Medicare Part D claims for anti‐anxiety, antidepressant and antipsychotic medications to determine prescriptions filled during 2017.

Result

Providers diagnosed anxiety and depression at higher rates in White patients; and psychosis at higher rates in Black patients. (P<0.001) Providers diagnosed female patients with depression, anxiety and psychosis at higher rates than males. (P<0.001) A provider diagnosis of anxiety, depression or psychosis is most prevalent in the age group 50‐59 and decreases with age to age 90+. Females with anxiety, depression and psychosis filled more anti‐anxiety and antidepressant medications than males. (P<0.001) Black and Other race patients filled more antipsychotic medications for anxiety and depression than White patients. (P<0.001)

Conclusion

Of concern is the high fill rate of anti‐anxiety (benzodiazepine) medications, especially in females. In patients with a neuropsychiatric diagnosis, consistently over half filled an antidepressant medication and over a quarter filled prescriptions for antipsychotics. These medications may have risks > benefits in this population and lack efficacy. As alternatives, non‐pharmacologic treatment with patient/caregiver education about expectations and psychosocial interventions show promise. Innovative community outreach and care delivery models incorporating these methods may help decrease levels of medication use.
Modeling the temporal evolution of plasma and PET Alzheimer’s disease biomarkers
Authors: Cogswell Petrice M , Lundt Emily S. , Therneau Terry M. , Graff‐Radford Jonathan , Schwarz Christopher G. , Senjem Matthew L. , Gunter Jeffrey L. , Knopman David S. , Vemuri Prashanthi , Petersen Ronald C. , Jack Clifford R.
Published: December 2023

Background

Knowledge of the temporal evolution among plasma Alzheimer’s biomarkers and PET will inform disease pathophysiology and appropriate implementation of plasma biomarkers (Therneau, NeuroImage 2021; Betthauser, Brain 2022). This study investigates the relative timing of progression of plasma p‐tau181, p‐tau217, GFAP, and amyloid PET on individual and population levels.

Method

We included 957 participants from the Mayo Clinic Study of Aging with clinical diagnoses of cognitively unimpaired (n = 732), MCI (n = 205), and Alzheimer’s clinical syndrome dementia (n = 20). An accelerated failure time (AFT) model was fit with amyloid (PiB) PET, plasma p‐tau217 (Meso Scale Discovery, Lilly), plasma p‐tau181, and GFAP (Simoa, Quanterix HD‐X) as quad‐variate endpoints, and sex, APOE genotype status, and education as covariates. The model output included a per subject adjustment or time‐shift for each biomarker indicating how much earlier or later it was estimated to progress relative to the average participant, the correlation (R) between adjustments for each pair of biomarkers, and the impact of covariates on each biomarker’s timing. Secondly, we estimated progression at a given age for selected cutpoints.

Result

Temporal trajectories for each biomarker are shown in Figure 1. Individual‐level adjustments between plasma p‐tau217 and amyloid PET were highly correlated, R = 0.69(0.64‐0.74); how early or late an individual progressed on plasma p‐tau217 explained 48% of the variation in relative timing of amyloid PET progression. Associations of plasma p‐tau181 and GFAP with amyloid PET individual adjustments were moderate and low, respectively (Figure 2). Using the chosen cutpoints, the estimated order of biomarker progression was GFAP, amyloid PET, plasma p‐tau181, and plasma p‐tau217 (Figure 3).

Conclusion

On the individual level, the strong association of the relative timing of progression of plasma p‐tau217 and amyloid PET supports that these processes are mechanistically related. The relatively lower associations of the timing of p‐tau181 and GFAP with amyloid PET likely reflect a lower biological association and greater measurement noise for p‐tau181. The individual adjustments, the primary output of this model, are independent of cutpoints. On the population level, relative timing of biomarker change is highly dependent on the cutpoints applied. This true for any analysis that employs cutpoints, regardless of the approach.
Cognitive Decline Associated with Longitudinal Changes in 24‐h Ambulatory Blood Pressure Variability
Authors: Melgarejo Jesus D , Vatcheva Kristina P. , Mena Luis Javier , Chavez Carlos A , Silva Egle , Calmon Gustavo , Mavarez Rosa P. , Lee Joseph H. , Terwilliger Joseph D. , Maestre Gladys E.
Published: December 2023

Background

Cognitive decline has been associated with variability in blood pressure (BP). However, whether the increment of the BP variability during follow‐up precedes cognitive decline remains undocumented. We aimed this study to investigate cognitive decline in relation to longitudinal changes in 24‐h reading‐to‐reading BP variability.

Methods

We conducted an observational longitudinal study that included 717 dementia‐free participants from the Maracaibo Aging Study who underwent follow‐up assessment in both 24‐h ambulatory BP monitoring and cognitive tests between 1998 and 2015. Cognitive domains consisted of selective reminding tests (total, long‐term, short‐term, and recognition memory) and the Mini‐Mental State Examination (MMSE). Cognitive decline was a longitudinal decrease in cognitive scores. Participants underwent 24‐h ambulatory BP monitoring between 2‐4 times – with at least one‐year interval. Systolic and diastolic BP variability was studied during 24‐h and divided into daytime (from 06h00 to 23h00), and nighttime (23h00 to 06h00) periods. To account for BP level, we used variability independent of the mean (VIM) to compute systolic and diastolic BP variability. Other measures of BP variability included the nocturnal BP drop in comparison to the daytime BP level, which was estimated as the night‐to‐day ratio. Statistics included multivariate linear regression mixed models.

Results

Overall, the mean age was 65.6±7.36 years old and 66.5% (n = 447) of the participants were women. In mixed models, a decline in all memory domains was associated with greater variability in the 24‐h, daytime, and nighttime systolic BP during follow‐up, with an estimated decline in cognitive scores ranging from ‐0.2 to ‐0.04 points per unit increase in VIM systolic BP during follow‐up (P values ranged from 0.022 to 0.003). Decline in total, short‐term, and MMSE memory domains was associated with greater 24‐h and daytime diastolic BP variability (P≤0.015). A lower night‐to‐day dipping ratio during follow‐up increased the risk of cognitive decline, with a ‐5.8 to ‐1.6 decline in long‐term memory and MMSE scores; respectively (P≤0.037).

Conclusions

Cognitive decline associates with greater reading‐to‐reading 24‐h BP variability and lower falls in nocturnal BP over time. These findings might be indicative of deteriorated regulatory mechanisms to maintain steady BP levels as individuals age.
A novel sociodemographically‐neutral speech analysis algorithm to detect cognitive impairment in a Spanish population
Authors: Gabirondo Peru , Coca Alberto , Kaser Alyssa , Schaffert Jeffrey , Cullum Munro , Raboso Javier Jiménez , Guardia Pablo , Lacritz Laura
Published: December 2023

Background

Early detection of mild cognitive impairment (MCI) and dementia is crucial for initiation of care. Brief, cost‐effective cognitive screening instruments are needed to identify individuals who require further evaluation. This study presents preliminary data on a new screening technology using automated recordings analysis software in a Spanish population.

Method

Data were collected from 148 Spanish‐speakings in Spain (MAge = 74.4, MEducation = 12.93, 43.3% males), clinically diagnosed as cognitively normal (CN, n = 78) or impaired (MCI, n = 49; all‐cause dementia, n = 21). Participants were recorded performing four language tasks [Animal fluency, alternating fluency (sports and fruits), phonemic “F” fluency and Cookie Theft Description]. Recordings were processed via text‐transcription and digital‐signal processing techniques to capture neuropsychological variables and audio characteristics. A training sample of 103 subjects with similar demographics (age, sex, education) across groups was used to develop an algorithm to detect cognitive impairment. The features of each task and of speech were used separately to develop five algorithms to compute scores between 0 and 1, and a final algorithm was constructed from these using repeated cross‐validation. Of the 45 remaining original participants, an age‐balanced subset of 28 subjects was used to test the algorithm. General linear modeling was used to quantify demographic biases in the data and in the predicted logistically‐transformed algorithm scores.

Result

Mean logit algorithm scores were significantly different across groups in both test/training samples (p<1e‐3). Sex‐bias in the test dataset (psex = 1.3e‐5) was reduced by predicted logit scores (psex = 0.01); other demographic variables were not significant across samples (page = 0.31→0.21; peducatiom = 0.69→0.58; pmultilingualism = 0.74→0.32). The final algorithm in test/training samples obtained an AUC of 0.908/0.956, with overall accuracy of 89%/89%, sensitivity of 0.85/0.95, and specificity of 0.92/0.83 in discriminating CN and impaired groups.

Conclusion

These findings provide initial support for the utility of this automated speech analysis algorithm as a screening tool for cognitive impairment that does not explicitly use memory tests. Further research is needed to validate algorithm in other languages and cultures.
Adult‐ and childhood onset dementias: related causes and related solutions?
Authors: Barthelson Karissa , Lardelli Michael , Hemsley Kim M
Published: December 2023

Background

The endo‐lysosomal pathway (ELP) of cells is central to their importation of nutrients and for recycling of cellular components. Much genetic evidence supports the importance of dysfunction of the ELP in Alzheimer’s disease (AD). However, AD is a complex disorder and how AD‐associated genetic variation affects ELP function is unclear. Sanfilippo syndrome childhood dementia is a consequence of extreme ELP dysfunction, where inherited recessive mutations result in the ELP’s inability to properly catabolise a particular polysaccharide. Unlike AD, Sanfilippo is genetically simple. All the causative genes have been identified and the biochemical consequences of their mutations are understood. Animal models of Sanfilippo are considered excellent models of the human disease. Using zebrafish as a model organism, we are dissecting shared disease mechanisms between these two dementia subtypes.

Method

Zebrafish models of both (early‐onset familial) AD and Sanfilippo syndrome were generated using CRISPR‐Cas9‐based approaches. The brain transcriptomes (RNA‐seq) and metabolomes (metabolomics/fluxomics) of both models are compared within single zebrafish families. Spatial working memory in both models is assessed using a Y‐maze.

Result

Preliminary brain transcriptome analyses have identified changes‐in‐common to both oxidative phosphorylation and ribosome gene expression in both AD and Sanfilippo model zebrafish. Metabolomics and behavioural analyses of these models are ongoing.

Conclusion

Neurodegeneration in Sanfilippo syndrome and Alzheimer’s disease may share common mechanisms that are amenable to common therapeutic approaches.
An optimized integrated functional genomics toolkit identifies novel role of SORL1 in microglia
Authors: Sher Falak
Published: December 2023

Background

Recent genome wide association studies implicated microglia in the pathophysiology of neurodegeneration; however, the translation of these genetic discoveries is hindered by the current lack of a robust human microglia in vitro model system and standardized protocols for functional genomics assessment. Though microglia differentiated from human induced pluripotent stem cells (iMG) could be a promising cellular model, the available differentiation protocols are variable, lengthy and give inefficient, mixed yields, limiting our ability to utilize modern gene editing tools (e.g., CRISPR‐Cas9) in this model for elucidating the functional consequences of disease relevant genes and variants.

Methods

In order to streamline microglia functional genomics, we optimized a highly efficient protocol to differentiate human induced pluripotent stem cells into iMG in two easy steps, offering a significant improvement in purity and time requirement for iMG production. We validated this iMG model system in a robust way through a comprehensive single cell RNA‐sequencing (scRNA‐Seq) study, mass spectrometry‐based proteomics and microglial functional assays. In addition, the iMG differentiation protocol includes sequential iMG harvesting and cell freezing steps, that will allow the researchers to scale up the production of iMG for high‐throughput assays. Furthermore, the toolkit also includes a drug inducible CRISPR‐ON/OFF approach in our newly established microglia model system that enables the investigation of gene function in a temporal fashion. All the data generated as part of the comprehensive validation is publicly available in the form of a searchable online platform (https://jasonchungngo.shinyapps.io/IPSC-derived-Microglia/).

Results

We used this newly developed integrated microglia functional genomics toolkit, along with human primary microglia freshly purified from dorsolateral prefrontal cortex (DLPFC), to investigate the thus far unidentified role of SORL1, an AD associated gene, in microglia. By combining state‐of‐the art (e.g. single cell RNA‐Seq, proteomics and focused CRISPR‐Cas9 screen) and standard (immunohistochemistry on postmortem human aged brain tissues) approaches we established the molecular mechanisms by which SORL1 shapes the functional phenotypes of human microglia. Most interestingly, we have found divergent roles for SORL1 in microglia when compared to neurons.

Conclusions

Our findings highlight the importance of cell type specific functional genomics of susceptibility genes in AD.
NEUROPROTECTIVE EFFECT OF PALIPERIDONE IN LPS INDUCED ANIMAL MODEL OF AD
Authors: Thakur Smriti , Sandhu Rajender , Deshmukh Rahul Renukadas
Published: December 2023

Background

Alzheimer’s disease is a progressive neurological condition, that impairs cognition and memory. Extracellular beta‐amyloid plaques and intracellular neurofibrillary tangle formation are the two hallmarks while cognitive decline, neurotransmitter deficit, neuroinflammation, mitochondrial dysfunction, decreased cerebral glucose uptake, and oxidative stress has been known to contribute to the pathogenesis of AD. The present study was designed to investigate the neuroprotective potential of Paliperidone on intracerebroventricular (i.c.v.) Lipopolysaccharide‐induced experimental dementia of Alzheimer’s type.

Method

LPS was administered by the i.c.v route on 1st day of the study in rats. Paliperidone was administered (1mg/Kg and 2mg/kg/day i.p) from the 1st to 21st day in LPS‐infused rats. Morris water maze, open‐field test, and object recognition parameters were used to assess learning, memory, behavioral changes and locomotor activity in rats. LPS infusion rapidly causes neuroinflammation and oxidative‐nitrosative stress.

Result

These markers were determined in the cortical and hippocampal brain regions of rats. While paliperidone treatment attenuates the LPS‐induced behavioral and biochemical abnormalities in rats by reducing levels of Malondialdehyde (MDA), reduced glutathione (GSH), and increasing levels of catalase. The neurodegeneration in Hippocampus and cortex regions was observed through histopathological examination. The observed cognitive improvement following paliperidone in LPStreated rats may be due to its antioxidant and anti‐inflammatory activity and restoration of cholinergic functions.

Conclusion

Our results suggest the therapeutic potential of paliperidone in cognitive disorders such as AD. However, more investigations are required to evaluate the potential of paliperidone in boosting memory and cognition and preventing neuronal damage.