bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of NLRP3 inhibitors for intervening in Alzheimer’s disease
Authors: Xu Yiming , Biby Savannah , Zhang Shijun
Published: December 2022

Background

NLRP3 inflammasome is an essential component of innate immunity, and its dysregulation has been linked to neuroinflammation and the development of neurodegenerative disorders including Alzheimer’s disease. Therefore, NLRP3 inflammasome represents a promising target for effective AD treatment development.

Method

Based on our newly identified lead NLRP3 inhibitor, a photoaffinity labeling probe was designed and employed to understand the mechanism of action for inhibitors based on this chemical scaffold using biochemical, biophysical, and molecular biology assays.

Result

The chemical probe can specifically recognize the NLRP3 protein from cell lysates. Photo‐affinity labeling studies using recombinant human NLRP3 protein also showed their interactions, and notably, the mode of action is different than other known NLRP3 inhibitors. Further characterization using FRET confirmed its interaction with the NLRP3 protein. Mass spectrometry analyses of the photo‐affinity labeled NLRP3 protein revealed a novel biding site with the NACHT domain of the NLRP3 protein.

Conclusion

Studies using a rationally designed photo‐affinity probe based on our lead NLRP3 inhibitor demonstrated that our inhibitors directly bind to the NLRP3 protein via a novel mechanism of action, distinct from other known NLRP3 inhibitors.
Mitochondrial Phenotypes in iPSC AD Models
Authors: Flannagan Kaitlin , Stopperan Julia A. , Troutwine Benjamin R , Lysaker Colton R , Strope Taylor A. , Draper Julia , Shaddy‐Gouvion Cynthia , Vivian Jay , Haeri Mohammad , Wilkins Heather M
Published: December 2022

Background

Mitochondrial dysfunction is observed in Alzheimer’s disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells. We examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. Postmortem brain tissue was used as a comparison.

Method

iPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer’s Disease Research Center (KU ADRC) cohort or purchased from WiCell. Postmortem brain samples were from the KU ADRC cohort when available. A total of four non‐demented and four sporadic AD iPSC lines were examined. Postmortem brain tissue was derived from 9 ND and 12 AD subjects. iPSCs were differentiated into neurons, astrocytes, or cerebral organoids using StemCell Technologies protocols and reagents. iPSC derived models and postmortem brain tissue were subjected to mitochondrial respiration analysis using Seahorse XF technology and spectrophotometric COX Vmax assays. iPSC derived neurons and astrocytes underwent fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, and mitophagy levels.

Result

iPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects. These results were not observed in astrocytes. Postmortem human brain samples showed reduced COX Vmax in AD subjects. iPSC derived neurons had reduced mitochondrial respiration parameters, mitochondrial mass, mitochondrial membrane potential, and mitochondrial superoxide production. iPSC derived astrocytes had reduced mitochondrial respiration parameters but increased mitochondrial membrane potential and no change in mitochondrial superoxide production.

Conclusion

iPSC derived models from AD subjects show mitochondrial dysfunction phenotypes like what is observed in postmortem brain. As iPSCs do not maintain their epigenetic signatures after reprogramming the observed phenotypes are likely due to other somatic factors.
Peroxiredoxin 6 Regulates Glia Toxicity in Tau Mediated Neurodegeneration
Authors: Pankiewicz Joanna E. , Lizińczyk Anita M , Franco Leor A. , Sadowski Martin J.
Published: December 2022

Background

In Alzheimer’s disease (AD) neurons, which accumulate hyperphosphorylated tau (p‐tau) are associated with neurodegenerative phenotype microglia (MGnD) and A1 neurotoxic astrocytes. MGnD display reduced ability to phagocytose p‐tau aggregates and neuronal remnants, while their pro‐inflammatory character furthers p‐tau accumulation and neuronal demise. Likewise, A1 astrocytes lose their neuron‐supporting function and promote neurodegeneration. Importantly, MGnD and A1 astrocytes reciprocally stimulate their pathological phenotypes. Factors protecting astrocytes form A1 phenotype transformation are unknown. In this work we explored the role of peroxiredoxin (PRDX) 6 in tau mediated neurodegeneration. PRDX6 is an enzymatic protein which in the CNS is unique to astrocytes. It possesses independent glutathione peroxidase and phospholipase 2 enzymatic activities, which confer ability to repair oxidatively damaged cell membranes and cell‐to‐cell signaling.

Method

MAPT
P301S mutant mice (PS19/Prdx6
+/+) were once crossed to Prdx6
‐/‐ mice and mice homozygous for the knock‐in of the Prdx6
129X1/SvJ allele overexpressing wild‐type PRDX6 to generate novel PS19/Prdx6
+/‐ and PS19/Prdx6
Tg lines, respectively. Eight weeks old PS19/Prdx6
+/‐, PS19/Prdx6
+/+, and PS19/Prdx6
Tg animals show 0.4:1:2 ratio of Prdx6 brain mRNA level, while levels of hTau and Gfap mRNA remain unchanged. Male mice were neuropathologically characterized at the age of 9.5 months.

Result

PS19/Prdx6
+/‐ mice feature increased hippocampal atrophy and ventricular enlargement and greater p‐tau accumulation compared to PS19/Prdx6
+/+ mice. Contrariwise, PS19/Prdx6
Tg animals show attenuated brain atrophy and p‐tau accumulation. The GFAP+ load used as a marker of global astrocytic activation and the C3+/GFAP+ ratio, used as a surrogate A1 phenotype marker, vary inversely with the Prdx6 gene dose. Likewise, the load of IBA1+ microglia vary inversely with the Prdx6 gene dose, while the CD68+/IBA1+ index, which determines relative microglia phagocytic activity, directly correlates with the Prdx6 expression.

Conclusion

Exacerbation of the pathological phenotype in PS19/Prdx6
+/‐ mice reveals a neuroprotective effect of PRDX6 in tau mediated neurodegeneration, while attenuation of pathology in PS19/Prdx6
Tg mice suggests a merit of therapeutic PRDX6 upregulation. PRDX6 endows astrocytes with resistance to A1 phenotype transition. Astrocytic PRDX6 also reprograms microglia by downregulating their global activation level and selectively promoting phagocytic properties. Comparative analysis of astrocytic and microglia transcriptomic markers across PS19/Prdx6
+/‐, PS19/Prdx6
+/+, and PS19/Prdx6
Tg genotypes is underway.
The etiology of blood‐based biomarkers for Alzheimer’s Disease in a population‐based sample of mid to late‐age males
Authors: Gillespie Nathan A. , Rissman Robert A. , Elman Jeremy A. , Reynolds Chandra A. , Panizzon Matthew S. , Lyons Michael J. , Neale Michael C. , Franz Carol E , Kremen William S.
Published: December 2022

Background

The amyloid‐tau‐neurodegeneration (ATN) framework has led to an increased focus on Alzheimer’s disease (AD) biomarkers. The costs and invasiveness of methods relying on cerebrospinal fluid or positron emission tomography imaging have led to efforts to develop sensitive blood‐based biomarkers. Although AD is highly heritable, the biometric genetic and environmental etiology of blood‐based biomarkers has never been explored.

Method

We therefore analyzed plasma beta amyloid (Ab40, Ab42, Ab42/40), total Tau (t‐tau), and neurofilament light (NFL) biomarkers based on a sample of 1,050 men aged 60 to 73 years (m=67.1, SD=2.57) from the Vietnam Era Twin Study of Aging (VETSA). Unlike AB and tau, NFL does not define AD; however, as a biomarker of neurodegeneration it serves as the N component in the ATN framework.

Result

Univariate analyses revealed that familial aggregation in Ab42, Ab42/40, t‐tau and NFL could be entirely explained by additive genetic influences accounting for 50% to 56% of the total variance. All remaining variances were unshared or unique environmental influences. For Ab40, additive genetic (31%) and shared environmental (44%) influences both contributed to total variance. In multivariate analyses, genetic influences accounted for 73% to 75% of the variance in the Ab biomarkers and 55% to 57% of the variance in t‐tau and NFL. The same analyses also revealed that Ab40 and Ab42 were statistically genetically identical and moderately correlated in terms of their environmental influences. All other bivariate associations ranged from small to moderate.

Conclusion

Our findings suggest that plasma biomarkers are heritable and that Ab40 and Ab42 share the same genetic influences. In contrast, genetic influences on plasma t‐tau and NFL are mostly unique and uncorrelated with plasma Ab in early old‐age men.
The rationale behind the IWG criteria for Alzheimer's disease
Authors: Dubois Bruno R
Published: December 2022

Background

The development of in‐vivo biomarkers has moved the diagnosis of Alzheimer’s disease from the dementia stage towards the prodromal stage, and has introduced the potential for preclinical diagnosis (ie, before symptom onset). These developments are relevant for the testing of potential therapies for secondary prevention of Alzheimer’s disease.

Method

Review of the literature

Result

In 2018, the US National Institute on Aging and the Alzheimer’s Association proposed a purely biological definition of Alzheimer’s disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice, at least for the supposely preclinical stage of the disease. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. This was previously underlined by neuropathologists who indicate a consensus to disentangle the clinic‐pathological term ‘Alzheimer’s disease’ from the presence of Alzheimer lesions in the brain in their ‘NIA‐AA guidelines for the neuropathological assessment of Alzheimer’s disease’. Furthermore, a positive Alzheimer’s disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer’s disease pathology is present as a comorbidity.

Conclusion

In line with these observations, the International Working Group recommend that Alzheimer’s disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer’s disease phenotypes, whereas biomarker‐positive cognitively unimpaired individuals should be considered only at‐risk for progression to Alzheimer’s disease.
Endpoints and outcomes: the challenge of biomarker choice for VCI trials
Authors: Winder Zachary , Sudduth Tiffany L , Patel Ela , Anderson Sonya , Neltner Janna , Bahrani Ahmed Ali , Abner Erin L , Nelson Peter T , Jicha Gregory A , Wilcock Donna M
Published: December 2022

Background

Clinical trials for Alzheimer’s disease (AD) have been significantly enhanced by the development of a suite of biomarkers ranging from PET and MRI modalities to CSF and now, plasma. Such biomarkers have refined trials by enabling the specific inclusion of participants with the targeted pathology. Clinical trials for vascular cognitive impairment and dementia (VCID) will require similar development and validation of biomarkers to be used for inclusion, stratification, target engagement, and efficacy in trials.

Methods

We have explored fluid biomarkers for VCID using two longitudinal cohorts: UK‐ADRC and MarkVCID. Using the Quanterix Simoa assays, we have examined) neurodegenerative (NfL), inflammatory (GFAP, IL1b, TNFa, IL6, IL10), and angiogenic (PlGF, VEGF‐A, MMP9) biomarkers in plasma. We examined associations of these plasma biomarkers with disease phenotypes: white matter hyperintensities (WMH) and cerebrovascular reactivity (CVR) on MRI, learning and memory assessments, and neuropathologic hallmarks including amyloid plaques, tangles, amyloid angiopathy (CAA), brain arteriolosclerosis and microinfarcts.

Results

In association with WMH, a presumed neuroimaging indicator of small vessel disease, we found that PlGF and WMH were positively correlated. Further, higher plasma GFAP was significantly associated with decreased CVR. For cognition, PlGF was associated with decreased attention and processing speed as assessed by Trail Making Test‐A; anti‐inflammatory cytokine IL10 was positively correlated with performance on verbal memory and verbal fluency. As has been shown previously, we observed that plasma NfL was negatively associated verbal fluency. Finally, when examining cerebrovascular pathologies, we found PlGF was positively associated with CAA, while GFAP was positively associated with chronic small vessel pathology like microinfarcts; IL8, an endothelial‐derived cytokine, was positively associated with more severe brain arteriolosclerosis.

Conclusion

A number of candidate plasma biomarkers have been identified for potential use in clinical trials for VCID and these warrant further validation and characterization. While angiogenic markers like PlGF were associated with WMH, small vessel pathology may be more strongly associated with inflammation as indicated by GFAP and IL8. Verbal memory and fluency may be negatively affected by inflammation, and NfL remains a robust biomarker for cognitive test performance.
Mitochondrial dysfunction in models of Progressive Supranuclear Palsy
Authors: Troutwine Benjamin R , Lysaker Colton R , Strope Taylor A. , Swerdlow Russell H , Wilkins Heather M
Published: December 2022

Background

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease hallmarked by tau pathology in both neurons and astrocytes. Familial forms of PSP are caused by mutations affecting tau (MAPT) while risk factors for sporadic PSP are largely unknown. Mitochondrial function declines during aging and mitochondrial dysfunction is observed in PSP. Generation of reactive oxygen species and mitochondrial dysfunction are thought to directly contribute to the production of tau deposits. Here we interrogated mitochondrial function in astrocytes and neurons derived from induced pluripotent stem cell models of sporadic and familial PSP.

Methods

Induced pluripotent stem cells were obtained from healthy controls, patients with sporadic PSP, and PSP patients carrying a MAPT A152T mutation. iPSCs were differentiated into neurons and astrocytes following StemCell Technologies protocols. Mitochondrial function was assessed using the Seahorse XFe96 analyzer. Fluorescent stains were used to determine mitochondrial mass, mitochondrial membrane potential, mitophagy levels, mitochondrial turnover, and mitochondrial calcium levels.

Results

Neurons derived from sporadic PSP and A152T tau patients had decreased mitochondrial respiration, increased mitochondrial superoxide, and increased mitochondrial mass. Astrocytes derived from sporadic PSP patients had increased mitophagy, mitochondrial turnover, mitochondrial calcium, and mitochondrial superoxide. Complex I and Complex IV activity were increased in sporadic PSP derived astrocytes, but in A152T tau astrocytes we observed decreased Complex I activity.

Conclusion

Neurons and astrocytes derived from PSP patients show changes in mitochondrial function. Alterations are cell type specific and differ between sporadic and familial PSP models. We are working to determine how this contributes to tau pathology.
Keep Your Brain HAP‐B: Group Psychoeducation to Promote Behaviors which Support Healthy Brain Aging
Authors: Trittschuh Emily H , Shryock Sarah Kelly , Hirschhorn Elizabeth W , Verstaen Alice
Published: December 2022

Positive health behaviors can promote brain health with age. We developed a novel health education and implementation group for older Veterans called the “Healthy Aging Project: Brain” also known as HAP‐B. We had these primary goals: provide psychoeducation, focus on ‘what matters’, improve awareness of health behaviors, and promote behavioral change through individualized goal‐setting, monitoring, and support. The scientific literature + needs assessment‐based content addresses 4 key areas: physical activity, sleep improvement, cognitive stimulation, and social interaction. Each of the 6 “classes” are 90 minutes long. Pre‐pandemic n=37 Veterans across 6 groups participated. To mitigate health risk exposure and reach Veterans for whom travel is a barrier, we have adapted the group to a virtual format with n=18 participants across 3 virtual groups (another group is ongoing, n=6). This QA/QI project collects optional pre/post self‐report measures which target satisfaction with the group, depressive symptoms, sleep quality, social support, and subjective well‐being. Additions along the way include in‐session self‐ratings for targeted goal behavior adherence and a pre/post self‐efficacy questionnaire. Our population tends to be predominantly male and White. Results and qualitative findings are promising. The group has successfully been run in 3 outpatient in‐person settings: Mental Health Services, Geriatrics Memory Health Clinic, and Primary Care Mental Health Integration. In‐person results suggest a significant decline in report of depressive symptoms. Lessons learned for implementation for both the in‐person and virtual formats will be shared, as well as analyses on associations between self‐efficacy and satisfaction with life over time. Future directions include ongoing data collection to increase power, continued efforts to increase participant diversity, and direct comparison of in‐person vs virtual formats. We will also present our initiated adaptation for flexible use in long‐term care facilities and among those with cognitive impairments.
A Visual Interpretation Algorithm for Assessing Brain Tauopathy with [18F]MK6240 Positron Emission Tomography
Authors: DuBois Jonathan M , Seibyl John , Racine Annie M , Collins Jessica A. , Martarello Laurent , Salinas Cristian A
Published: December 2022

Background

In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials in Alzheimer’s disease (AD). [18F]MK‐6240 is a radiotracer with high selectivity and sub‐nanomolar affinity for neurofibrillary tangles. Here, we developed a visual assessment that provides a binary outcome for tau deposition, as well as a semi‐quantitative metric of the extent of regional tau deposition in the brain.

Method

Data included 214 subjects (AD, HC, MCI, and other disorders) who underwent [18F]MK‐6240 PET scans, which were used to generate 70‐90 min static images. Half of the subjects were reviewed by an expert nuclear medicine physician blind to participants’ diagnosis to identify common patterns of brain uptake. Based on this review, a visual read method was developed for testing in a separate cohort of 102 subjects, which included two additional independent readers. Visual read outcomes were compared with quantitative ROI analysis.

Result

Readers demonstrated a high level of concordance for binary regional outcome, with all three‐reader in agreement on 74.3% of scans with a Fleiss’s k=0.912. Readers showed excellent intra‐reader reproducibility, with two readers attaining 10/10 self‐agreement and one reader attaining 9/10 agreement. Relative to clinical diagnosis, readers showed a sensitivity of 76‐81% and specificity of 91‐92%. Mean cortical SUVr was higher in read positive (2.17/0.91) than to negative (1.02/0.18) scans.

Conclusion

We developed a read algorithm permitting both binary determination and the regional extent of abnormal tau. These cross‐sectional results demonstrate feasibility, which might allow for further evaluation of progressive tau changes in AD.
Cohort effects in mild to moderate AD trials: an empirical assessment utilizing data from the Alzheimer’s disease cooperative study
Authors: Birnbaum Adam , Gillen Daniel L. , Grill Joshua
Published: December 2022

Background

Heterogeneity in patient populations can impact clinical trial conclusions and generalizability. Long recruitment windows may exacerbate this in Alzheimer’s disease (AD) trials, which often recruit over extended periods.

Method

We used data from 8 Alzheimer’s Disease Cooperative Study (ADCS) clinical trials (DHA, Homocysteine, Huperzine, Intravenous Immunoglobulin, Resveratrol, Valproate, NSAIDs, and FYN Kinase inhibitor) in patients with mild to moderate AD to investigate cohort effects by time‐of‐trial‐enrollment.

For each participant, we assigned a study‐ and site‐specific enrollment time defined as the number of days between a patient’s screening and the first screening visit at the site. We used study‐ and site‐specific time origins to account for calendar time differences between studies and, within a study, differences in site times to activation.

To investigate differences in baseline characteristics, we split our sample into tertiles by enrollment time and compared sex, race and ethnicity, age, years of education, and baseline scores on the Alzheimer’s Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog).

To assess cohort effects on trial outcomes, we used the 12‐month within‐subject change in ADAS‐Cog. We regressed the 12‐month change in ADAS‐Cog on a patient’s enrollment time while controlling for their baseline score and demographic information and allowing for clustering between patients in the same study.

Result

Groups were demographically similar at baseline across enrollment tertiles. We found a significant difference in 12‐month change in ADAS‐Cog for patients with different enrollment times: later enrolled patients had an expected 12‐month change in ADAS‐Cog 0.146 points higher than similar patients who enrolled one quarter (91.2 days) earlier (95% CI: 0.082‐0.210). This magnitude of difference was roughly on par with an additional year of education. We also found a negative relationship with age, with older patients tending to experience a smaller 12‐month decline.

Conclusion

In these 8 trials, we found minimal evidence of cohort effects that would meaningfully change study generalizability or treatment effect. Future analyses will account for the overall pace of accrual in the trials and assess for potential differential effects in fast vs. slow‐accruing studies.
Deep Sleep Time Measured by Wearable Device Associated with Amyloid Burden in the Elderly with Subjective Cognitive Decline.
Authors: Park Kee Hyung , Yang Dong Won , Hong Yun Jeong , Kim Ahro , Ho SeongHee , Jeong Jee Hyang , Kim SangYun , Choi Seong Hye , Han SeungHyun
Published: December 2022

Background

Factors other than age and genetics may influence the development of Alzheimer’s disease. In particularly, there is growing evidence that sleep disturbances are associated with increased β‐amyloid burden. We investigated the association between sleep characteristics measured with a wearable device and β‐amyloid burden in the elderly diagnosed with subjective cognitive decline.

Method

We conducted a cross‐sectional study in 76 elderly people over 60 years of age with subjective cognitive decline determined by detailed neuropsychological tests. β‐amyloid burden was determined by F18‐florbetaben positron emission(PET) using two methods. Firstly, visual rating of BAPL (Brain amyloid plaque load) score was used to determine β‐amyloid positivity. Secondly, the SUVR (standardized uptake value ratio) values were used for the quantitative evaluation of β‐amyloid deposition. Sleep characteristics including total sleep time, number of awakenings during sleep, REM sleep time, deep sleep time, and light sleep time were measured using a wearable device. In addition, we investigated the association between β‐amyloid burden and age, ApoE4 genotype, MMSE, and PSQI.

Result

Of the 76 subjects included in the analyses, 64.5% were women. The subjects were 70.7 (±6.09) years of age at the beginning of the study. Fifteen subjects were positive and 61 were negative on F18‐florbetaben PET. The average SUVR value was 1.27 (±0.220). In particular, we found that deep sleep time was significantly higher in the β‐amyloid‐negative group (49.5±13.1 minutes) than in the positive group (39.4±13.1 minutes). (p‐value 0.009)

Conclusion

According to our analysis, a decrease in deep sleep time appears to be associated with amyloid deposition. This is consistent with recent evidence that sleep disturbances may be associated with increased β‐amyloid burden. A large‐scale prospective study is needed to clarify the causal relationships between deep sleep and amyloid deposition.
Soluble TAM receptor biomarkers: Neuroprotection in AD neuroinflammation?"
Authors: Brosseron Frederic , Maass Anne , Kleineidam Luca , Ravichandran Kishore Aravind , Peters Oliver , Priller Josef , Schneider Anja , Fließbach Klaus , Wiltfang Jens , Duzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Teunissen Charlotte E. , Synofzik Matthis , Wagner Michael , Jessen Frank , Ramirez Alfredo , Ruiz Agustin , Heneka Michael T.
Published: December 2022

Background

While neuroinflammation is reckoned as a pathological hallmark of AD, research on suitable biomarkers is still ongoing. Here, we report on findings from the DZNE DELCODE, Fundacío ACE and other cohorts demonstrating distinct inflammatory biomarker profiles in CSF and serum. Intriguingly, within these profiles, soluble TAM receptor markers are elevated in neurodegeneration but still relate to protection of cognition and brain structure.

Method

We investigated a panel of 20 experimental biomarkers utilizing customized immunoassays in CSF and serum samples of DELCODE and other cohorts with a total of >1000 subjects, including healthy controls, subjective cognitive decline, mild cognitive impairment, AD relatives and AD patients. Data were analyzed in relation to clinical and biomarker‐based staging as well as cognitive and structural imaging composite scores, adjusted for covariates such as age.

Result

Various inflammatory markers, when measured in CSF, were found to correlate to tau isoforms and other neurodegeneration markers and to be elevated in pre‐dementia stage subjects with already pathological tau levels. Among these, soluble TAM receptors sAXL and sTyro3 were related to preserved cognition and brain structure. In serum, inflammatory markers displayed different interrelations, with individual proteins in serum showing no or modest correlation to their CSF counterparts or other AD biomarkers. Noteworthy, serum soluble AXL increased only in AD subjects and related to decreased structure and function.

Conclusion

Neurodegeneration in AD is accompanied by a pattern of elevated inflammatory CSF biomarkers. These proteins likely represent cellular responses to neuronal damage and are evident already at pre‐dementia stages of disease. Within this response, upregulation of TAM receptors in the brain could serve to regulate neuroinflammation and promote cellular survival, with receptor turnover resulting in elevated CSF levels. Noteworthy, blood signatures of the same biomarkers, though not without significance, show different patterns of relations towards disease features, likely reflecting distinct peripheral cellular origins and biological functions of the respective proteins. These findings point towards TAM signalling as potential target for future therapeutic intervention, especially in subjects with pre‐dementia neurodegeneration phenotypes. As such, CSF soluble TAM levels might provide promising readout biomarkers.
Midlife plasma proteome‐wide analysis identifies peripheral immune networks associated with 25‐year dementia risk
Authors: Walker Keenan A , Chen Jingsha , Shi Liu , Yang Yunju , Fornage Myriam , Zhou Linda , Schlosser Pascal , Surapaneni Aditya , Grams Morgan E , Duggan Michael R , Peng Zhongsheng , Gomez Gabriela , Tin Adrienne , Hoogeveen Ron C , Sullivan Kevin J , Ganz Peter , Lindbohm Joni V , Kivimaki Mika , Nevado‐Holgado Alejo J , Buckley Noel , Gottesman Rebecca F , Mosley Thomas H , Boerwinkle Eric , Ballantyne Christie M , Coresh Josef
Published: December 2022

Background

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer’s disease (AD) and related dementias. However, there is limited understanding of the biological pathways mechanistically relevant in the earliest phase of disease and a lack of protein biomarkers available to capture the biological systems involved.

Method

To discover early biomarkers and further understand on a molecular level the systemic factors that may promote neurodegeneration, we used a large‐scale proteomic platform to relate 4,877 plasma proteins measured in middle‐aged adults to dementia risk over a 25‐year period (n=10,981; 1,874 incident dementia cases) in the Atherosclerosis Risk in Communities (ARIC) study (Figure 1). Dementia‐associated proteins were related to 20‐year cognitive decline in the Whitehall II study, and to AD risk and CSF biomarkers European Medical Information Framework‐AD study.

Result

Proteome‐wide association study in ARIC discovered 32 midlife dementia‐associated plasma proteins, the majority of which were involved in either immune function, proteostasis/autophagy, or extracellular matrix organization (Figure 2). We replicated the relationship between candidate proteins and neurocognitive outcomes in multiple independent cohorts and demonstrated a relationship between dementia‐associated plasma proteins and cerebrospinal fluid markers of Aß42, p‐tau181, neurodegeneration, and neuroinflammation (Figure 3). Using network analysis, we identified 19 co‐expressed protein modules, 4 of which were strongly associated with either short‐term and long‐term dementia risk (Figure 4). Pathway analyses conducted for the dementia‐associated protein modules suggested dysregulation of specific immune pathways (e.g., JAK‐STAT signaling, Toll‐like receptor activation) and disrupted proteostasis/autophagy and extracellular matrix organization during midlife ∼20 years before dementia onset, and abnormal coagulation/complement signaling ∼10 years before dementia onset (Figure 5). We used two‐sample Mendelian randomization to identify which midlife plasma proteins and protein networks may play a mechanistic role in Alzheimer’s disease, and demonstrated that many of the dementia‐associated proteins may play a causal role in systemic inflammatory and autoimmune diseases associated with heightened AD/dementia risk.

Conclusion

This work sheds light on the complexity of the systemic immune response in the decades preceding dementia onset and highlights multiple potential biomarkers and therapeutic targets for early AD.
Diagnostic and Prognostic Performance of the Modified Lumipulse pTau 181 Assay in Plasma for Alzheimer’s Disease
Authors: Wilson Edward N. , Young Christina B , Benitez Javier A. Ramos , Vandijck Manu , Swarovski Michelle S. , Shahid Marian , Corso Nicole , Kennedy Gabriel , Trelle Alexandra N , Channappa Divya , Belnap Malia , Lind Betty , Bastard Nathalie Le , Quinn Joseph F , Nairn Angus C , Kerchner Geoffrey A. , Sha Sharon , Wagner Anthony D , Henderson Victor , Longo Frank M. , Wyss‐Coray Tony , Poston Kathleen L , Mormino Elizabeth C. , Andreasson Katrin I.
Published: December 2022

Background

Recent advances demonstrate utility in blood‐based phosphorylated tau (pTau) as a diagnostic biomarker for Alzheimer’s disease (AD). While several platforms show high diagnostic and prognostic performance, most assays rely on antibody combinations that require long tau peptides for their detection. The Lumipulse G Plasma pTau 181 assay (Fujirebio) instead uses an antibody combination targeting epitopes proximal to Thr181 and therefore can detect shorter tau peptides. This allows for a wider array of expressed plasma pTau 181 peptides to be measured.

Method

Plasma pTau 181 was measured in three cohorts using the modified Lumipulse G Plasma pTau 181 assay: cohort 1 included 269 cognitively unimpaired (CU), 109 mild cognitively impaired (MCI), and 80 AD participants from the Stanford Alzheimer’s Disease Research Center (ADRC); cohort 2 included 192 CU from the Stanford Aging and Memory Study (SAMS); and cohort 3 a third, independent plasma cohort from the Yale University ADRC included 20 CU and 20 AD participants. Outcome measures included discriminative accuracy of the modified assay for clinical AD diagnosis, association with amyloid and tau pathology determined using CSF biomarkers or positron emission tomography (PET), and ability to predict longitudinal cognitive change.

Result

Plasma pTau 181 showed robust clinical performance in differentiating AD from CU participants in cohort 1 (AUC = 0.934) and cohort 3 (AUC = 0.845). In cohort 1, the analyte associated with CSF pTau 181 (β=+0.543 and P<0.001), CSF Aβ42/Aβ40 ratio (β=‐0.349 and P<0.001), and amyloid‐PET global SUVRs (β=+0.494 and P<0.001). Associations between plasma P‐tau181 with CSF and PET biomarkers were significant when examined in Aβ+ and Aβ‐ groups separately. Plasma pTau181 was also found to associate with inferior temporal tau‐PET in the subset of CU in cohort 2 (N=35, β=+0.393 and P=0.016). Finally, in cohort 1 baseline plasma pTau 181 predicted change in MoCA over 2‐year follow‐up, controlling for clinical diagnosis, age, sex, and education (β=‐0.211 and P=0.009).

Conclusion

The results across these 3 participant cohorts revealed the modified Lumipulse G pTau 181 assay discriminates AD pathology in clinical and preclinical AD, strongly associates with CSF and PET imaging in Aβ+ and Aβ‐ participants and predicts longitudinal cognitive decline.
Anterior hypothalamic pathology in Alzheimer’s disease: A human postmortem study using spatial in‐situ proteomics
Authors: Son Gowoon , Mladinov Mihovil , Pereira Felipe Luiz , Li Song Hua , Tu Chia‐Ling , Spina Salvatore , Seeley William W. , Chang Wenhan , Grinberg Lea T.
Published: December 2022

Background

The anterior hypothalamus contains several sleep‐promoting nuclei, including the suprachiasmatic nucleus (SCN), the key circadian clock in the brain. Sleep disturbances are a common in Alzheimer’s disease (AD), but little is known about the profile of AD‐related pathology in the anterior hypothalamic nuclei.

Method

We used the GeoMx Digital Spatial Profiling (DSP), an in‐situ spatial proteomics platform (Nanostring) to assess spatially resolved tauopathy and tau‐driven protein alteration in the SCN, supraoptic nucleus (SON), and periventricular nucleus (PV) in the anterior hypothalamus of four postmortem brains from three AD subjects and one control. The profiled regions‐of‐interest were confirmed by immunohistochemistry.

Result

All three nuclei showed significantly higher levels of p‐tau 404 and 396 in AD than control, and differential patterns of selective vulnerability for tau, with the SCN, expressing greater p‐tau 404 and 396 levels than the SON. In addition, the p‐tau immunoreactivity corresponds to the DSP data. Interestingly, the PV indicated upregulated β‐amyloid(1‐42) and β‐secretase 1 than others.

Conclusion

AD patients revealed increased p‐tau expression in the SCN located in the anterior hypothalamus. Given that tau pathology is one of the main features in AD, altered p‐tau level may lead the SCN and other hypothalamic protein alteration shown in this result, influencing the hierarchical clustering. We suggest tauopathy can be a preceding criterion for tau‐driven hypothalamic protein subpopulation, explaining AD‐driven neurodegeneration and dysfunction such as sleep dysregulation in AD.
Plasma Biomarkers of Neurodegeneration and Tau in Relation to Longitudinal Depressive Symptoms in Older Adults: Findings from the Harvard Aging Brain Study
Authors: Gatchel Jennifer R , Yang Hyun‐Sik , Mimmack Kayden J. , Arnold Steven E. , Blacker Deborah , Liu Lei , Selkoe Dennis J , Johnson Keith A. , Sperling Reisa A. , Marshall Gad A , Chhatwal Jasmeer P.
Published: December 2022

Background

Depressive symptoms are common in late life and Alzheimer’s Disease (AD) but the underlying neurobiology of these symptoms and their relationships to AD biomarkers is unclear. Probing these relationships using biomarkers of neurodegeneration and tau that can be measured via plasma can importantly guide AD prognosis and treatment. The current study determined the relationships between baseline measures of neurofilament light (NfL) (a marker of neurodegeneration) and an N‐terminal fragment of tau (NT1, an early and specific marker of AD) and longitudinal depressive symptoms in a cohort of older adults.

Method

Longitudinal data were analyzed from 342 participants from the Harvard Aging Brain Study, an observational cohort study of individuals who were cognitively unimpaired and with no/minimal depressive symptoms at baseline (age: 71.7 +/‐ 8.1; % female: 61%; average follow up: 3.94 years, range: 0–7.88). Depressive symptoms were assessed annually with the 30‐item Geriatric Depression Scale (GDS). At study baseline, all participants had plasma samples assayed for NfL and NT1 and underwent amyloid (PiB) PET imaging to derive a cortical amyloid composite. Linear mixed effects models were used to examine relationships between dependent variable longitudinal GDS (log‐transformed) and predictors of interest: (plasma NfL or NT1) x time, and covariates: age, sex, education. Secondary models were adjusted for cortical amyloid and examined the interactive effects of amyloid and plasma biomarkers on longitudinal GDS.

Result

Higher baseline NfL predicted increasing GDS scores over time (β = 0.04 +/‐0.01, t = 3.8, p = 0.0001), while a trend was observed for NT1 (β = 0.02 +/‐0.01, t = 1.9, p = 0.06). Similar results were obtained when adjusting models for amyloid x time (NfL x time: β = 0.04 +/‐0.01, t = 3.8, p = 0.0002; NT1 x time: β = 0.02 +/‐0.01, t = 1.7, p = 0.09). Neither NfL nor NT1 interacted with amyloid to predict increasing GDS over time.

Conclusion

Findings support an association between depressive symptoms and plasma measures of neurodegeneration–whether cause or consequence. Moreover, for NfL, this relationship is independent of amyloid, suggesting that multiple pathways may underlie the emergence of depressive symptoms in older adults. Further longitudinal investigation in relation to cognition and across depressive symptom severity is needed to better understand the pathophysiology of depression in late life and AD.
Blood pressure postural changes variability is associated with cognitive decline: the S.AGES cohort
Authors: Strumia Mathilde , Vidal Jean‐Sebastien , Hanon Olivier , Rouch Laure
Published: December 2022

Background

Over the past decade, higher blood pressure (BP) variability has been associated with cognitive decline (CD). To date, only one study investigated the specific impact of visit‐to‐visit BP postural changes variability on dementia but its association with cognition is still unknown. We aimed to investigate the association between BP postural changes variability and cognitive function in noninstitutionalized subjects aged ≥ 65 years.

Method

The S.AGES (Sujets Âgés) cohort followed for three years noninstitutionalized subjects aged ≥ 65 years without major neurocognitive impairment at inclusion. At each visit, an orthostatic systolic BP (SBP) ratio was calculated using the formula (sitting SBP/standing SBP) x 100. An orthostatic diastolic BP ratio was computed using the same method. Subjects with a SBP ratio > 100% had sitting SBP > standing SBP. We assessed the visit‐to‐visit BP postural changes variability according to several indicators: standard deviation, coefficient of variation (CV), variation independent of mean, residual standard deviation, average real variability, and successive variation. Cognitive performances were evaluated using the Mini‐Mental State Examination. Linear mixed models were used for the analyses.

Result

We included 2,974 subjects (mean age 78 years, women 56%). After adjustment for age, sex, education, baseline body mass index, smoking, alcohol intake, atrial fibrillation, congestive heart failure, transient ischemic attack or stroke, coronary artery disease, type 2 diabetes, dyslipidemia, seated SBP/DBP and antihypertensive treatment, greater visit‐to‐visit systolic BP postural changes variability was significantly associated with CD over time (adjusted β [95% CI] = ‐0.17 [‐0.29; ‐0.06], p = 0.004 for CV). Similar results were found for visit‐to‐visit diastolic BP postural changes variability (adjusted β [95% CI] = ‐0.14 [‐0.25; ‐0.03], p = 0.017 for CV).

Conclusion

Greater visit‐to‐visit BP postural changes variability was associated with CD. Further studies are needed to assess whether controlling orthostatic BP instability over time could be a promising interventional target to preserve cognition among older adults.
Polymorphisms in the WWOX gene are associated with brain glucose metabolism and influence cerebrospinal fluid p‐tau181 levels
Authors: Salles Giovanna Bortoluzzi , De Bastiani Marco Antônio , Povala Guilherme , Souza Diogo O. , Zimmer Eduardo R. , de Souza Débora Guerini
Published: December 2022

Background

Genome‐wide association studies (GWAS) studies can be a powerful tool for identifying new single nucleotide polymorphisms (SNPs) associated with multifactorial diseases. Previous GWAS have identified more than 20 genes as potential factors of genetic susceptibility in Alzheimer’s disease (AD). One of them is the protein coding gene WW Domain Containing Oxidoreductase (WWOX), which is highly expressed in mature astrocytes and neurons. Here, we investigated the association between WWOX SNPs, 18F‐FDG PET neuroimaging and cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 181 (p‐tau181) in elderly individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Methods

Data was acquired from 537 participants (CU= 195; MCI= 314; AD= 28) of the ADNI database. The brain glucose metabolism was estimated using the standard uptake value ratio (SUVr, cerebellum as reference) of FDG‐PET. The presence of the SNPs were integrated to FDG PET images using voxel‐wise generalized linear regression models adjusted for age, gender, diagnostic status, and years of education (RMINC package). Through the Wilcoxon test we determined if the SNPs presence influenced p‐tau181 levels in CSF. All statistical analyzes were performed in the R statistical computing software (version 4.1.2) (significance level of p < 0.05).

Results

Sixty‐seven WWOX SNPs were statistically associated with 18F‐FDG PET signal. Voxel‐wise analyses demonstrated that the top ten WWOX SNPs with the highest number of voxels altered in the FDG‐PET images were associated with cortical hypermetabolism (Figure 1, top three). Thirteen WWOX SNPs were significantly associated with lower p‐tau181 concentration in the CSF, including rs7193539 (p = 0.0004), rs7206890 (p = 0.0061), and rs11859281 (p = 0.0009), compared to the reference genotype.

Conclusion

Several SNPs of the WWOX gene were significantly correlated to brain metabolism. The presence of the SNPs can influence p‐tau181 levels, suggesting a role of WWOX in AD, as reported in other previous studies. Our findings suggest a protective effect of these WWOX gene variants. Additional studies are needed to better understand the biological implications of our findings.
Gait Correlates of Cognitive Function and Future Decline
Authors: Tipton Philip W , Ali Farwa , Syrjanen Jeremy A. , Graff‐Radford Neill R. , Machulda Mary M. , Fields Julie A. , Vemuri Prashanthi , Jack Clifford R. , Mielke Michelle M. , Boeve Bradley F. , Jones David T. , Graff‐Radford Jonathan , Knopman David S. , Petersen Ronald C. , Savica Rodolfo
Published: December 2022

Background

Slow walking speed is associated with numerous negative health outcomes including global cognitive decline.1 More detailed gait analysis can differentiate among different dementia subtypes,10 but the predictive power of baseline gait metrics for domain‐specific cognitive decline needs further characterization.

Method

We conducted a follow up study on 534 participants of the Mayo Clinic Study of Aging who underwent evaluations every 15 months (median follow‐up = 5.4 years). We analyzed quantitative gait metrics, acquired with a pressure‐sensing walkway (GAITRite® instrument), and cognitive scores using a linear mixed effects model to identify correlations between z‐scored baseline gait metrics (cadence, swing time, stance time, velocity, double support time (DST), stride length, stride length standard deviation (SD), stride time SD, swing time SD, stance time SD, DST SD) and cognitive domain z‐scores (memory, attention, language, visuospatial, global) at baseline and over time. Models controlled for age, sex, and probable REM sleep behavior disorder at baseline.

Result

The table includes both baseline associations and difference in slopes (Δ), relative to the average person, in cognitive domains. These slopes ranged from about ‐0.05 for visuospatial to ‐0.12 for attention.

Conclusion

Increased gait velocity and stride length are associated with less severe domain‐specific and global cognitive decline while increased swing time SD and DST are associated with more severe rates of decline in some domains. These findings suggest that baseline gait characteristics could be a helpful predictor of future cognitive changes.

References:

1. Savica R, Wennberg AMV, Hagen C, et al. Comparison of Gait Parameters for Predicting Cognitive Decline: The Mayo Clinic Study of Aging. Journal of Alzheimer's disease : JAD. 2017;55(2):559. doi:10.3233/JAD‐160697

2. Mc Ardle R, del Din S, Galna B, Thomas A, Rochester L. Differentiating dementia disease subtypes with gait analysis: feasibility of wearable sensors? Gait & Posture. 2020;76:372–376. doi:10.1016/j.gaitpost.2019.12.028
Nurse Practitioner Follow‐Up Care Using Telehealth MMSE
Authors: Palumbo Mary Val , Greenough Victoria , Rambur Betty , Callas Peter W
Published: December 2022

Background

During the COVID‐19 pandemic, many healthcare services moved to telehealth delivery for continuation of care. The Mini Mental Status Examination (MMSE) has been used for follow‐up assessment of disease progression and care planning after dementia diagnosis. Carotentuto et al. (2018) found no difference in MMSE scores when repeating a telehealth MMSE two weeks after a face‐to‐face visit. The purpose of this study was to determine if telehealth cognitive testing (MMSE) is a reliable alternative to traditional face‐to‐face testing when nurse practitioners are providing follow‐up care (every 6 months) for person with dementia and their families.

Methods

To evaluate MMSE testing administered via telehealth, a retrospective chart review of patients (N = 90) seen between April 2020 and December 2021 was conducted. Those fitting the inclusion criteria of at least two previous face‐to‐face MMSE assessments, and two MMSE telehealth assessments were analyzed (n = 45). Linear regression calculated the slope for each patient’s MMSE score per year to compare the face‐to‐face and telehealth rates of cognitive decline for each individual. A paired t‐test was used to compare MMSE slope for face‐to‐face and telehealth assessments.

Results

Although there was a larger decrease per year in MMSE score across telehealth assessments (during the pandemic) when compared to in‐person (‐2.7 vs ‐1.2, respectively), the difference in individual decline was not statistically significant (p = 0.10). There was also no significant difference between MMSE slope of decline in each of the two nurse practitioner providers for in‐person testing mean (p = 0.32), telehealth mean (p = 0.34) and difference in slopes (p = 0.27).

Conclusion

These preliminary findings indicate that administering the MMSE via telehealth does not result in scores that are markedly different from in‐person testing. Therefore, it is reasonable to use telehealth for follow‐up dementia care visits when an objective measure of cognitive decline is helpful to guide family caregiving. Telehealth may be a good alternative for patients and family who are unwilling or unable to travel to the clinic due to health concerns, poor weather, long travel time or agitation in a clinic setting, even when the pandemic has ended.