bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel role of microRNA‐9 in stimulating mature BDNF and reducing cellular REST level in human fetal brain derived primary neuron culture.
Authors: Wang Ruizhi , Maloney Bryan , Counts Scott E. , Lahiri Debomoy K
Published: December 2022

Background

Alzheimer's disease (AD) and Parkinson's disease are the most common neurodegenerative diseases. As of a 2021 report, the Alzheimer's Association estimates that the number of Americans with AD could be as many as 6.2 million. However, how the patho‐biochemical changes are regulated at the cellular level is still largely unknown.

Our goal is to devise ways to arrest and/or reverse neurodegeneration. Our objective is to determine the molecular pathway in promoting neuronal survival. MicroRNA (miRNA), a group of small non‐coding RNAs, regulates multiple biological and pathological processes by binding to target mRNAs, the disruption of which could contribute to AD pathogenesis. Our hypothesis is to determine the role of a specific miRNA that can promote neural survival and neuronal gene expression. Our aim is two‐fold. First is to increase levels of BDNF, which is a neurotrophic factor. This protein promotes the survival of nerve cells by playing a role in the growth, maturation (differentiation), and maintenance of these cells. Second goal is to de‐repress neuronal gene expression by reducing REST protein. Can these aims be achieved by using one micro‐RNA? Here we show miR‐9's ability to exert both these actions in a beneficial way.

Method

Human primary cortical neurons, astrocytes and differentiated neuroblastoma were transfected with miR‐9. Cells lysate and culture media were harvested. Western blotting and ELISA were performed to determine target protein levels. Well‐defined human brain autopsy samples from AD patients and healthy elders were assayed for mature BDNF.

Result

Treatment with synthetic miR‐9 mimics stimulated secretion of mature BDNF in human primary cortical ReN cells. Under the same condition, miR‐9 treatment decreased levels of nuclear Repressor Element 1‐Silencing Transcription factor (REST) protein. Treatment with antisense to miR‐9 (antagomiR) reversed the effect of miR‐9 on mBDNF and REST levels.

Conclusion

MiR‐9 increased mBDNF while reducing REST. REST is known to silence neuronal genes and BDNF to promote neural survival. Due to the twin impacts: increasing BDNF and decreasing REST, miR‐9 plays a vital role in neuron’s vitality and health. The further experiment would determine whether miR‐9 treatment would protect neuronal against insults that lead to neurodegeneration.
Olfactory dysfunction but not COVID‐19 severity predicts severity of cognitive sequelae following SARS‐CoV‐2 infection in Amerindian older adults
Authors: Gonzalez‐Aleman Gabriela , Zamponi Hernan P. , Juarez‐Aguaysol Leonardo , Kukoc Gabriela , Dominguez Maria Eugenia , Pini Belén , Padilla Eduardo G , Calvó Maria , Molina‐Rangeon Silvia Beatriz , Guerrero Gonzalo , Figueredo‐Aguiar Mariana , Fumagalli Emiliano , Vaca Fabiana , Yécora Agustín , Brugha Traolach S , Seshadri Sudha , Snyder Heather M. , de Erausquin Gabriel A. ,   Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2
Published: December 2022

Background

COVID‐19 has affected more than 380 million people. Infections may result in long term sequelae, including neuropsychiatric symptoms. In older adults COVID‐19 sequelae resemble early Alzheimer’s disease, and may share risk factors and blood biomarkers with it. The Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) established harmonized definitions, ascertainment and assessment methodologies to evaluate and longitudinally follow up cohorts of older adults with exposure to COVID‐19. We present one year data in a prospective cohort from Argentina.

Method

Participants (n = 766) are older adults (≥60 years) recruited from the provincial health registry containing all SARS‐CoV‐2 testing data. We randomly invite older adults stratified by PCR COVID‐19 testing status regardless of symptom severity, between 3 and 6 months after recovery. Assessment includes interview with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Clinical Dementia Rating scale (CDR); neurocognitive assessment; emotional reactivity scale; and neurological assessment including semiquantitative olfactory function test, motor function, coordination and gait.

Result

We assessed 88.4% infected participants and 11.6 % controls. Education is 10.36 ± 5.6 years and age is 66.9 ± 6.14 years. Level of care during COVID‐19 is described in Figure 1. Normalized cognitive Z‐scores categorize the cohort in 3 groups with decreased performance compared to normal cognition: memory only impairment (Single‐domain,11.7%); impairment in attention+executive function without memory impairment (Two‐domain, 8.3%); and multiple domain impairment (Multiple domain,11.6%). Logistic regression showed that severity of anosmia, but not clinical status, significantly predicts cognitive impairment. No controls had olfactory dysfunction. Cognitive impairment is defined as Z‐scores below (‐ 2) (Table 1). Clinical assessment with SCAN revealed functional memory impairment in two thirds of infected patients (CDR ≥ 1), which was severe in half of them. Phone‐based follow up at 1 year revealed high adherence (4 participants declined). Five were deceased at follow up. Rates of re‐infection (between 10 and 23%) were not affected by the vaccination schedule (Table 2).

Conclusion

The longitudinal cohort had very high adherence. Persistent cognitive and functional impairment after SARS‐CoV‐2 infection is predicted by persistent anosmia but not by the severity of the initial COVID‐19 disease.
Associations between local area deprivation and physical activity in cognitively impaired people: an accelerometry study
Authors: Ardle Ríona Mc , Hamilton Calum , Din Silvia Del , Kingston Andrew , Robinson Louise , Galna Brook , Thomas Alan J , Rochester Lynn
Published: December 2022

Background

Empowering people with cognitive impairment (PwCI) to maintain physical activity (PA) supports functional independence. PwCI participate in less PA than recommended; disease‐specific factors (e.g. cognitive changes) do not sufficiently explain this. In older adults, most habitual PA takes place in the home or local neighbourhoods. Targeting PA in both the home and local community may be more impactful than creating external opportunities (e.g. exercise classes).

Regular participation in PA requires time, money, security, and access. Area deprivation may contribute to inequalities in PA participation through environmental factors; less deprived areas may have safer walkable routes and more immediate socialisation opportunities which support PA. Understanding the complex relationship between local area deprivation and PA may support personalised care for PwCI. We aimed to explore associations between local area deprivation in the North East of England and PA in PwCI and cognitively‐intact older adults (controls).

Method

We recruited 82 PwCI (mild cognitive impairment, dementia) and 26 controls. Daily step count was measured using an accelerometer worn on the lower back continuously for seven days. We derived mean daily step counts for each individual day. Individuals’ neighbourhoods were linked to UK government area deprivation statistics. Hierarchical Bayesian models assessed the association between area deprivation and daily step count in PwD and healthy older adults.

Result

Preliminary results indicated that greater area deprivation is associated with lower daily steps for cognitively‐healthy older adults (12,308 (8,302‐19,111) steps/day for controls in least deprived areas, vs 9,349 (5,178‐17,444) steps/day in most deprived areas), but not for PwCI (9,018 (7,042‐11,565) steps/day for PwCI in least deprived areas vs 9,124 (6,553‐12,435) steps/day in most deprived areas), who had consistently low step counts across neighbourhoods (Figure 1).

Conclusion

Cognitive impairment may impose a barrier to maintenance of habitual PA which supersedes the positive or negative influences of area deprivation on PA in cognitively healthy older adults. Findings are limited by lack of regional diversity and statistical power; further research should examine area deprivation across the whole of the UK to ensure accurate representation of area deprivation. PA interventions should consider multiple socio‐ecological factors, including personal, organisational, environmental and policy‐related components.
Cognitive impairment in COVID‐19 Survivors: Analysis and Extensions on Population Studies in Greece
Authors: Vavougios George D. , Stavrou Vasileios , Mysiris Dimitrios , Boutlas Stylianos , Papayianni Eirini , Koromboki Eleni , Mavridis Theodore , Astara Kyriaki , Biagi Nicolo , D'Avossa Giovanni , Katshu Mohammad Zia Ul Haq , Artemiadis Artemios , Hadjigeorgiou Georgios M. , Xiromerisiou Georgia , Zarogiannis Sotirios G , Daniil Zoe , Gourgoulianis Konstantinos
Published: December 2022

Background

The aim of our study was to investigate the prevalence and associations of cognitive impairment in COVID‐19 survivors in the post‐acute setting.

Method

Our study is conducted in three post‐COVID‐19 outpatient clinics in tertiary hospitals in Greece. Eligible subjects included previously hospitalized COVID‐19 survivors with mild to moderate disease, returning for follow‐up at least two months post‐discharge. Exclusion criteria included intensive care unit admission, intubation, a history of neurodegenerative disease and other significant comorbidities. Study measurements included demographics, clinical evaluation, medical, family history, anthropometrics, 6‐minute walk test (6MWT), 30 seconds sit‐to‐stand (30STS), handgrip strength, spirometry, Pittsburgh Sleep Quality Index (PSQI), the Montreal Cognitive Assessment (MoCA), reactive oxygen metabolites (dROMs) and plasma antioxidant capacity (PAT). Cognitive impairment was considered on MoCA ≤24.

Result

142 COVID‐19 survivors were included in the study (110 Male, 32 Female; Mean age of 56.16±10.92). A total of 47.2% presented with cognitive decline (CD) as indicated by a MoCA score ≤24. Cognitive decline prevalence by SARS‐CoV‐2 variant of concern (VOC) was 39.5%, 50% and 62.5% for Alpha, Beta and Delta, correspondingly. A binary logistic regression model controlling for age, gender and VOC indicated that the diffusing capacity for carbon monoxide (DLCO) was independently associated with MoCA ≤24 (p = 0.014, OR = 0.669, 95%CI: 0.484‐0.923). Compared to severe untreated OSAS (n = 28), distinct domains but similar prevalence of cognitive impairment was noted.

Conclusion

Diffusion capacity abnormalities for carbon monoxide in COVID‐19 survivors as noted in other studies, may be implicated in the development of cognitive impairment.
Enabling implementation of Blood based biomarkers in our healthcare systems
Authors: Teunissen Charlotte E. , Hansson Oskar , van Harten Argonde C.
Published: December 2022

Background

The novel blood based biomarkers have shown such promising results, and these developments coincide with the approval of the first AD drugs. This needs to consider clinical implementation. Are we there yet? What steps need to be undertaken to make that happen? Can we implement these biomarkers, as single markers or as combinations in secondary care, primary care, or in‐between to avoid health care system overload?

Method

This presentation will give an overview of steps be taken and currently ongoing.

Result

I will address clinical studies in different settings, technical developments on the level of assays and standardization of lab‐protocols and regulatory approval. In addition, i will discuss possible context of use and definition of appropriate use recommendations by the Alzheimer Association working group.

Conclusion

The exact context and appropriate use of BBB are to be defined in the next few years.
A methodology for normalizing fluid biomarker concentrations across reagent lots
Authors: Henson Rachel L. , Volluz Katherine , Saef Benjamin A. , Sutphen Courtney L. , Herries Elizabeth M. , Morris John C. , Fagan Anne M. , Xiong Chengjie , Schindler Suzanne E.
Published: December 2022

Background

Longitudinal studies of cerebrospinal fluid (CSF) and plasma biomarkers typically require the use of different assay reagent lots over time. Measured biomarker concentrations may drift from lot to lot, adding variability that may bias estimates and decrease the statistical power of biomarker analyses. Including lot as a covariate in models may not adequately adjust for lot effects, particularly if cohort characteristics change over time.

Method

CSF and plasma samples were collected from participants enrolled in studies of memory and aging. CSF Aβ40, Aβ42, total tau (t‐tau), and phosphotau‐181 (p‐tau181) were measured using a fully automated assay platform (LUMIPULSE, Fujirebio). CSF and plasma NfL were measured using a plate‐based ELISA (UMAN Diagnostics) and Simoa‐HDX assays (Quanterix), respectively. “Bridging” samples were measured using an initial lot of reagents and were subsequently re‐analyzed using a different lot of reagents. Biomarker concentrations were transformed with the natural logarithm and compared via linear regression. If the slope (tested against 1) or intercept (tested against 0) were significantly different, the equation for the initial values as a function of the subsequent values was used to normalize the subsequent values, putting all values on one common scale.

Result

Measured concentrations for all analytes were highly correlated between lots. Slopes and/or intercepts for a linear regression of the log(initial value) as a function of the log(subsequent value) were significant for CSF Aβ40 (intercept: p<0.0001), t‐tau (slope: p<0.0001), p‐tau181 (intercept: p<0.0001), and plasma NfL (intercept: p=0.001), but were not significant for CSF Aβ42 or NfL.

Conclusion

There is significant systematic variation in measured biomarker concentrations by reagent lot, even when using fully‐automated assay platforms. Running samples in larger batches with fewer lots is preferable to reduce lot effects. Using biomarker data unadjusted for lot effects or adjusted using simple correction factors may be problematic. Including two or three certified reference standards may not adequately control for these differences; measuring more samples across a wide range of values is likely necessary. Normalization of measured values between reagent lots may decrease variability in longitudinal data collected over several years, increase statistical power and improve the validity of biomarker analyses.
Association between PTSD and Cognitive Performance: A Longitudinal Twins Study
Authors: Kulshreshtha Ambar , Shah Amit , Ko Yi‐An , Goldberg Jack , Smith Nicholas , Jajeh Nour , Ahmed Hashir , Marof Biwar , Murrah Nancy , Shallenberger Lucy , Driggers Emily , Bremner Douglas , Vaccarino Viola
Published: December 2022

Background

Posttraumatic Stress Disorder (PTSD) is a chronic psychiatric condition that develops after exposure to life‐threatening events. The negative impact of PTSD on a person’s emotions and behavior can have long‐term deleterious effects on cognitive performance. The association between PTSD and cognition however can be confounded by unmeasured factors such as shared genetic and environmental factors. Twin studies allow us to explore this potential causal pathway by controlling for genetic and familial confounding.

Methods

We examined 77 male monozygotic and 47 dizygotic twin pairs from the Vietnam Era Twin Registry in two examinations approximately 12 years apart. At both visits, we obtained information regarding demographic data, medical history, diagnosis of PTSD and cognitive tests. Memory and learning were measured by Trail making tests, Wechsler Memory Scale (Immediate and Delayed Memory tests and Visual Reproductive Test). Linear mixed‐effect regression models were used to examine the association between PTSD and cognitive tests accounting for twin pairing. Analysis was performed by treating twins as individuals and considering within twin pair differences (among twin pairs discordant for PTSD).

Results

The mean age was 55 years (SD 3.0) at baseline, 96% were White, and 60% monozygotic twins. Lifetime history of PTSD was not associated with cognitive measures at baseline. At follow‐up, the mean age was 67.9 years (SD 2.5). In twins considered as individuals lifetime history of PTSD was associated with worse performance on Trails A (β = 4.9, 95% CI 8.6, 1.3, p‐value = 0.008) and Trails B (β = 14.6, 95% CI 26.8, 2.4, p‐value = 0.019). After adjusting for demographics, cardiovascular and behavioral risk factors, these associations persisted (Trails A, β = 5.4, 95% CI 9.4, 1.4, p‐value = 0.009; Trails B, β = 14.1, 95% CI 26.9, 1.2, p‐value = 0.032). The within‐pair estimates were similar to individual estimates. There was no association with Wechsler immediate or delayed story recall or Visual Reproductive Test. In stratified analyses, the results were similar by zygosity.

Conclusions

Lifetime history of PTSD is associated with poor cognitive performance, primarily in the executive function domain, which manifests at older age. This association is not confounded by shared genetic and other familial factors.
Antecedents of episodic memory in the oldest‐old: a population‐based NONAGINTA study with 45‐years of follow‐up
Authors: Vuoksimaa Eero , Varjonen Anni , Schwarz Claudia , Aaltonen Sari , Iso‐Markku Paula , Palviainen Teemu , Urjansson Mia , Rinne Juha O. , Kaprio Jaakko
Published: December 2022

Background

We have established NONAGINTA – Memory and Health in 90‐year‐olds –study in a population‐based sample with 45 years of follow‐up. Our study is aimed to understand both, the antecedents of cognitive impairment and successful cognitive aging in the oldest‐old (90 years or older).

Method

Participants were nonagenarians from a population‐based longitudinal older Finnish Twin Cohort study with baseline questionnaire in 1975. Ongoing 90‐year‐old data collection included postal questionnaire and telephone administered cognitive testing. Episodic memory (EM) was measured with total words recalled in three trials of 10‐word list. Predictors of EM included cognitive, health‐related, and psychological factors. Self‐reported educational attainment, body mass index (BMI), physical activity (METhours/day), life satisfaction and neuroticism were measured in middle age (N = 55, age M = 46.2, SD = 1.7 years) and in old age (N = 59‐67, age M = 91.3, SD = 1.9 years). Semantic verbal fluency (number of animals in 1‐minute) and depressive symptoms (Center for Epidemiological Studies – Depression (CES‐D)) were measured only in old age. We used individual level linear regression models with age and sex as covariates and adjusted for family structure.

Result

To date, 67 individuals have cognitive data. On average, women (N = 36, M = 11.97, SD = 4.70) had better EM than men (N = 31, M = 11.10, SD = 4.74), but this difference was not statistically significant (p = 0.49). Better verbal fluency was significantly related to better EM (r = 0.34, p<0.001). Compared to those with 6 years of education, those with 7‐11 years and those with 12 or more years of education had significantly better EM: 4.03 (95%CI: 1.27‐6.80) (p = 0.005) and 5.75 (95%CI: 3.75‐7.45) (p<0.001) words more, respectively. Mean CES‐D was 12.3 (SD = 8.7) and 16% scored above the cut‐off for clinically significant depressive symptoms, however, depressive symptoms were not related to EM (p = 0.15). Middle age or old age BMI, physical activity, life satisfaction or neuroticism were not significantly related to EM (p’s >0.32).

Conclusion

Our preliminary results suggest that cognitive, but not midlife or old age physical or psychological health‐related factors, are associated with episodic memory performance in nonagenarians. Good episodic memory goes hand in hand with good semantic fluency and cognitive benefits of early life educational attainment are still evident in nonagenarians.
Linking amyloid to clinical outcome: A quantitative semi‐mechanistic model based on the A/T/N biomarker framework to simulate the natural history of Alzheimer’s disease and the effects of anti‐amyloid treatment
Authors: Mazer Norman A , Hofmann Carsten , Lott Dominik , Gieschke Ronald , Klein Gregory , Boess Frank , Grimm Hans Peter , Kerchner Geoffrey A. , Baudler Monika , Smith Janice , Schobel Scott , Doody Rachelle S.
Published: December 2022

Background

According to FDA’s literature review of clinical trial data from a number of anti‐amyloid antibodies, a “clear relationship” was demonstrated between the extent of amyloid plaque removal measured by amyloid PET and the magnitude of clinical benefit measured by the placebo‐corrected difference in the CDR sum of boxes (CDR‐SB). To understand this relationship from a theoretical perspective we developed a quantitative semi‐mechanistic representation of the A (amyloid)/T (tau)/N (neurodegeneration) framework (the Q‐ATN model) in order to simulate the natural history of disease progression and the effects of anti‐amyloid therapy.

Method

Published data and biologically plausible mechanisms were used to construct, calibrate and validate the components of the Q‐ATN model (anti‐amyloid effect, amyloid PET, tau PET, cortical thickness [CT] and clinical outcome [CDR‐SB]). A parabolic input function was used to describe the annual rate of increase of the amyloid PET level in placebo patients (in Centiloids/Yr) as a function of the baseline level. Clinical trial simulations corresponding to mean treatment responses were made for different anti‐amyloid antibodies using individualized pharmacokinetic (PK) and pharmacodynamic (PD) models of the anti‐amyloid effect. A 5‐Yr simulation of gantenerumab treatment, based on the dosing regimen employed in the ongoing phase 3 GRADUATE trials (NCT03444870; NCT03443973), was performed to illustrate the predicted long‐term effects of gantenerumab maintained at the target dose.

Result

The simulated time‐course of biomarkers and clinical outcomes were consistent with natural history studies and described the effects of several anti‐amyloid antibodies observed in trials with positive and negative outcomes. Figure 1A‐D shows the simulated 5‐Yr time‐course of gantenerumab and placebo treatment on A. amyloid PET; B. tau PET; C. medial temporal cortical thickness and D. CDR‐SB. The model predicts that the difference in CDR‐SB between active and placebo groups increases markedly with the time of treatment, reaching ‐5.2 units at the 5‐Yr endpoint of the simulation.

Conclusion

The Q‐ATN model provides a novel theoretical approach for linking amyloid to clinical outcome based on the A/T/N framework. It illustrates the predicted disease‐modifying potential of gantenerumab – with increasing treatment benefits over time. The predictions of the Q‐ATN model will be compared with forthcoming clinical trial data.
Incident Dementia and Long‐Term Exposure to Constituents of U.S. Fine Particle Air Pollution: A National Cohort Study
Authors: Shi Liuhua
Published: December 2022

Background

Growing evidence suggests that PM2.5 likely increases the risks of neurological disorders, yet little is known about the relative contributions of different constituents. Understanding constituent‐specific effects are critical to targeting emission reductions of specific sources with the greatest health protection.

Method

We conducted a nationwide population‐based cohort study (2000‐2017), by integrating the Medicare Chronic Conditions Warehouse database and two sets of high‐resolution, multiple‐species, air pollution datasets to investigate the impact of long‐term exposure to PM2.5 constituents on incident dementia and Alzheimer’s disease (AD). and home health‐care claims. Hazard ratios for dementia and AD were estimated using single‐ and multi‐constituent Cox proportional hazards models, and penalized splines were used to evaluate potential nonlinear concentration‐response relationships.

Results

Of the 18.5 million dementia and 19.2 million AD individuals within these cohorts, 31.5% and 14.6% developed dementia and AD events, respectively. From the single‐pollutant models, an interquartile range (IQR) increase in PM2.5 mass was associated with an increase in dementia incidence ranging between 6‐7% using two exposure datasets. For different PM2.5 constituents, associations remained significant in black carbon (BC), organic matter (OM), sulfate (SO4
2−), and ammonium (NH4
+). Incident dementia was observed to have the strongest association with increases in exposure to SO4
2− and BC (10‐11% increase and 4‐6% per IQR increase, respectively). Effect estimates for AD were even larger. For both endpoints, all constituents had largely linear concentration‐response relationships in the low exposure range, but most tailed off at high exposure concentrations, particularly for AD.

Conclusion

Our study suggests that long‐term exposure to PM2.5 is significantly associated with increased incident dementia and AD, and that the different PM2.5 constituents may elicit differential neurotoxicity. Reduction of PM2.5 emissions, especially for the main sources of BC and SO4
2−, may reduce the burden of dementia or AD in the aging US population.
Medial temporal lobe subregional atrophy patterns in early‐ and late‐onset amnestic Alzheimer’s disease
Authors: Wuestefeld Anika , Wutt Hmon , Baumeister Hannah , Berron David , Binette Alexa Pichet , Stomrud Erik , Mattsson‐Carlgren Niklas , Strandberg Olof , Smith Ruben , Palmqvist Sebastian , van Westen Danielle , Hansson Oskar , Wisse Laura EM
Published: December 2022

Background

The medial temporal lobe (MTL) is hypothesized to be relatively spared in early‐onset compared to late‐onset Alzheimer’s disease (AD). However, detailed examination of MTL subfields comparing amnestic early‐ and late‐onset AD is lacking. We investigate MTL subfield atrophy patterns in individuals with amnestic early‐ and late‐onset cognitive impairment (EOCI and LOCI).

Methods

Cognitively impaired (mild cognitive impairment and dementia) adults from the BioFINDER‐2 study with memory impairment (>1.5SD age‐ and education‐specific norms), amyloid‐beta (Aβ+ based on CSF Aβ42/40), and tau positivity were included (Table 1). [18F]RO948‐PET standardized uptake value ratios (SUVRs) were calculated for the MTL, and tau‐PET positivity was determined from a temporal meta‐ROI. EOCI individuals were <65 years, LOCI >70 years of age. Self‐reported age‐of‐onset matched with EO/LO status. Two reference groups of Aβ‐ cognitively unimpaired (CU) which were age‐matched to EOCI/LOCI were included. Hippocampal subfield volumes and thickness of entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex were obtained using Automated Segmentation for Hippocampal Subfields packages for T1‐ and T2‐weighted MRI. We focused particularly on BA35, region with earliest tau accumulation. Episodic memory was determined (errors on delayed word‐list recall).

Results

Compared to CU, LOCI showed widespread atrophy across all MTL subfields, while the atrophy pattern in EOCI was slightly more restrictive (Fig. 1). Compared to EOCI, LOCI showed more severe atrophy in hippocampal subfields and entorhinal cortex.

There was no difference between EOCI and LOCI for MTL tau‐PET SUVR (Fig. 2).

Zooming in on BA35, there was a trend for an association between MTL tau‐PET SUVR and BA35 atrophy in LOCI. This association was stronger for EOCI but non‐significant, likely due to limited power (Fig. 2C). In both groups, smaller BA35 was associated with worse episodic memory (Fig. 3A). In LOCI, higher MTL tau‐PET SUVR was associated with worse episodic memory (Fig. 3B).

Conclusion

The findings suggest that MTL tau‐PET uptake and atrophy is present in both amnestic LOCI/EOCI and is related to the observed memory impairment in these groups. The MTL atrophy pattern is more extensive in LOCI, which may be due to longer presence of tau pathology and/or the involvement of comorbid pathologies.
Spatial proteomics in the hippocampi of resistant and resilient individuals as compared to Alzheimer’s disease (AD) and primary age‐related tauopathy (PART).
Authors: Walker Jamie M. , Ajroud Kaouther , Gong Jingjing , Spencer Callen , Zamudia Carlos , Pladies Erica , Solano Leigh , Bieniek Kevin F , Seshadri Sudha , Castellani Rudolph J , Richardson Timothy E. , Flanagan Margaret E
Published: December 2022

Background

An intriguing group of individuals, termed “resilient,” demonstrate neuropathologic changes consistent with Alzheimer disease (AD), yet display no cognitive impairment. In addition, there are older individuals who resist the development of AD neuropathologic change despite their age, termed “resistant.” Herein, we analyzed protein expression in the hippocampi around normal and neurofibrillary tangle (NFT)‐bearing neurons in these resistant and resilient individuals as compared to those with AD and primary age‐related tauopathy (PART) with cognitive decline.

Method

Utilizing Nanostring’s GeoMx™ Digital Spatial Profiling (DSP) technology, we compared individuals with AD neuropathologic change and dementia to individuals with AD neuropathologic change and no dementia (resilient), as well as PART with dementia and resistant (PART without dementia) cases. The DSP panel allows for spatial analysis of the level of expression of 73 different proteins in multiple regions of interest (ROIs) on formalin‐fixed paraffin‐embedded sections. We analyzed hippocampal sections, with our ROIs being NFT‐bearing neurons, non‐NFT‐bearing neurons, and their surrounding microenvironments (non‐neuronal cells and neuropil), including a comparison of entorhinal cortex, CA1 and CA2 subregions (Figures 1 and 2).

Result

Analyses comparing NFT‐bearing neurons to non‐NFT‐bearing neurons, revealed 22 proteins with differential expression, including various p‐tau epitopes, Neprilysin, ADAM10, IDE and GPNMB (Figure 3). Comparing resilient and AD NFTs, we identified 17 proteins with differential expression, including Park 5, HSC70 and VPS35 (Figure 4). The microenvironment of the resistant compared to others highlighted several proteins with differential expression including GFAP, NRGN and NEFL (Figure 5). A comparison of NFT‐bearing neurons in non‐demented cases displayed regional protein expression differences between entorhinal and CA1 including alpha‐synuclein and CSF1R. Distinct regional protein expression differences in NFT‐bearing neurons in demented cases were also identified including EMP1 and ATG12 (Figure 6).

Conclusion

In conclusion, using a novel spatial proteomic technique, we have demonstrated that resistant and resilient individuals display lower levels of inflammation and upregulation of protective pathways, that in turn lead to maintenance of neuronal integrity. In addition, although the resistant and resilient harbor PART and AD pathology (respectively), we have identified protein expression differences that may further our understanding of the mechanisms by which the resistant and resilient evade cognitive decline.
Neurofilament light chain cannot be measured in urine to distinguish frontotemporal dementia with primary psychiatric diseases
Authors: van Engelen Marie‐Paule E. , Heijst Hans , Willemse Eline A.J. , Oudega Mardien L , Vermunt Lisa , Scheltens Philip , Vijverberg Everard G.B. , Pijnenburg Yolande A.L. , Teunissen Charlotte E.
Published: December 2022

Background

Clinical overlap of the behavioral variant of FTD and primary psychiatric diseases (PPD) hampers diagnostic distinction, leading to frequent misdiagnosis and diagnostic delay. NfL in CSF and blood has shown great potential to accurately distinguish bvFTD from PPD and controls. Measurement of NfL in urine would be a minimal invasive, patient‐friendly biomarker assessment and thereby beneficial for future clinical implementation. We aimed to evaluate the diagnostic value of urine NfL concentration to distinguish bvFTD from PPD and controls and to assess if urine and serum NfL levels correlate.

Method

55 subjects (n = 19 FTD, n = 19 psychiatric patients: functional neurologic disorder n =2; obsessive compulsive disorder n= 1; unspecified mental disorder n =1; bipolar disorder, depressive phase n =1; depression, n = 6; adjustment disorder n = 3; anxiety disorder n = 1; autism spectrum disorder n =1; personality disorder n =2; somatic symptom disorder n = 2, and n = 17 controls) were included with available paired urine and serum samples. All subjects underwent standardized extensive diagnostic assessment. Samples were analyzed with the ultrasensitive SIMOA NfL assay. NfL group comparisons were performed adjusted for age and sex.

Results

In the majority of the cohort NfL concentrations were not detectable in urine (n = 6 samples above lower limit of detection (0.038 pg/ml): n = 5 FTD, n =1 PPD). The frequency of a detectable NfL level in urine in the FTD (5/19) group did not differ from PPD (1/19); Fisher Exact‐test p = 0.180). In the individuals with detectable urine NfL values there was no correlation between the urine and serum NfL levels. As expected, serum NfL levels were higher in bvFTD compared to psychiatric patients and controls (p < 0.000), adjusted for age and sex.

Conclusion

Our results implicate that using urine as matrix for NfL analysis is not suitable.
Association of Apathy with Amyloid‐β and Tau in Cognitively Unimpaired Older Adults: Findings from the Harvard Aging Brain Study
Authors: Katz Zoe S , Mimmack Kayden J. , Marshall Gad A , Blacker Deborah , Amariglio Rebecca E. , Munro Catherine E , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A. , Yang Hyun‐Sik , Gatchel Jennifer R
Published: December 2022

Background

Apathy is one the most common neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) and is associated with elevated AD pathology in cognitively impaired individuals. However, it remains unclear if apathy is associated with AD pathology, specifically amyloid‐β and tau, in cognitively unimpaired (CU) older adults. Therefore, we examined cross‐sectional relationships between apathy and neuroimaging AD biomarkers in CU older adults from the Harvard Aging Brain Study (HABS).

Method

HABS is a prospective cohort study that enrolled CU older adults. A random subset of HABS participants (n = 142, age: 80.53 ±6.0, 57% female) and their study partners (SP) completed the Apathy Evaluation Scale‐Self (AES‐S) and ‐Informant (AES‐I). The AES consists of 18 items rated on a 4‐point Likert‐type scale; lower scores indicate greater apathy. We used Pittsburgh Compound B (PiB) PET cortical composite distribution volume ratio to measure amyloid‐β (Aβ), and flortaucipir (FTP) PET standardized uptake value ratio in two regions (bilateral entorhinal (ER) cortex and inferior temporal (IT) cortex) to capture regional tau. We assessed the association of AES‐S or AES‐I (dependent variable) with Aβ, or each of the two regional tau values (independent variable), in linear models adjusting for age, sex, and education. We then explored Aβ‐independent associations between regional tau and AES‐I/AES‐S, by additionally adjusting for Aβ in each tau model.

Result

Elevated Aβ (β = ‐3.7, p = 0.015) and ER Tau (β = ‐6.0, p = 0.016) were associated with lower AES‐I, while IT tau was not (p = 0.14). None of the AD pathology measures were associated with AES‐S (all; p>0.23). ER tau was no longer associated with AES‐I once Aβ was also adjusted for in the model (β = ‐4.4, p = 0.100).

Conclusion

Greater Aβ and tau levels were associated with higher apathy in CU older adults. Our findings imply that even in CU older adults, apathy is closely related to AD pathology may be more accurately measured by study partner report than self‐report, which may reflect a measurement property of this NPS. Further study of apathy in preclinical stages is needed to provide understanding of potential interventions to prevent or delay behavioral symptoms of AD.
The gut microbiome is associated with markers of cerebral small vessel disease
Authors: Fongang Bernard , Satizabal Claudia L , Kautz Tiffany F , Himali Jayandra J , Ramnik Xavier , Cavazos José E. , Mahaney Michael C , Maestre Gladys E , DeCarli Charles S. , Vasan Ramachandran S , Seshadri Sudha
Published: December 2022

Background

Cerebral small vessel disease (cSVD) is a major cause of cognitive impairment and dementia in the elderly. Dysregulation of the gut microbiome has been linked to cSVD, stroke, and dementia in human and animal studies. However, whether dysbiosis is associated with markers of cSVD is unclear. We aimed to assess the cross‐sectional association between the gut microbiome and MRI markers of cSVD and executive function in the Framingham Heart Study (FHS).

Method

We included FHS participants from the Third‐generation cohort without a history of stroke or dementia. We estimated the gut microbiota composition using 16S rRNA gene sequencing. MRI markers of cSVD included white matter hyperintensities (WMH) and peak width of skeletonized mean diffusivity (PSMD). Executive function was assessed as the difference between the Trail Making Test (TMT) part B and A. We used multivariable regression analysis to evaluate the association between the gut microbiota and WMH, PSMD, and TMT, adjusting for age, age2, sex, BMI, and education. Additionally, we used differential abundance analysis to explore extremes of cSVD markers dichotomized by their distribution with the upper quintile representing the least healthy group. Finally, we used PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) to gain insight into the functional profiles of the underlying microbial communities.

Result

Our sample included 972 participants (age: 55 ± 10 years, 56% female). Using multivariable models, we found that greater abundance of genera Pseudobutyrivibrio and Ruminococcus were associated with lower (healthier) WMH and PSMD (p‐values < 0.001), as well as better executive function (p‐values < 0.01). Furthermore, the differential analysis indicated a lower abundance of the genus Prevotella in the group of participants with the highest (least healthy) PSMD and WHM (p‐values < 0.05). Finally, functional analyses using PICRUSt implicated various KEGG pathways, including carbohydrate metabolism, glycosaminoglycan, and fatty acid biosynthesis previously associated with cognitive performance.

Conclusion

Our study suggests abundance of certain gut bacteria in genus Pseudobutyrivibrio, Ruminococcus, and Prevotella, that produce butyric acid and other metabolites used by the human brain, are associated with healthier brain vasculature and better cognitive function in middle‐aged healthy adults.
Phenotyping of lenses from eyes of P301S tau mice
Authors: Moncaster Juliet A , Minaeva Olga , Goldstein Lee E
Published: December 2022

Background

We previously discovered that Aβ accumulates in the supranuclear region of the lens in the eyes of people with Alzheimer’s Disease (AD) (Goldstein et al., 2003) and Down Syndrome (DS; (Moncaster et al., 2010) and also in the Tg2576 APP swedish mutation AD mouse model (Moncaster et al., 2022). Aβ interacts with crystallin proteins in the lens to create light scattering aggregates that eventually manifest as cortical cataracts. Tau has previously been reported to be expressed in the lens of the eye (Bai et al., 2007; Zhao et al., 2013). Here we investigated whether cataracts may develop in the P301S tau model.

Method

P301S mice were bred and maintained at Boston University School of Medicine. Breeder mice were purchased from Jackson Laboratories, Bar Harbor, ME. Male and Female transgenic and non‐transgenic mice (n = 5‐6 per group) were sacrificed at ages 12‐13 months. This timepoint was chosen as it is the limit of lifespan for P301S transgenic mice. Mice were perfused with phosphate buffer saline, lenses were isolated and then imaged under two different sources of light using a D70 digital Nikon camera and a custom‐adapted Zeiss stereophotomicroscope.

Result

There was no overt difference in lens phenotype between the P301S transgenic and non‐transgenic mice. No cataracts were observed in these lenses at 12‐13 months of age.

Conclusion

There was no overt difference in lens phenotype between the P301S transgenic and non‐transgenic mice. Based on our current and previous results, the data suggests that Aβ may play a more significant role in lens pathology in AD than tau.
Using Proteomics Analysis to Identify Cerebrospinal Fluid Biomarkers in Normal Pressure Hydrocephalus
Authors: LaCasse Kathryn , de Geus Matthijs B , Trombetta Bianca A. , Ramirez Christopher E. , El‐Mufti Leena H. , Riley Misha M. , McManus Alison J. , Wills Anne‐Marie , Kivisäkk Pia , Carlyle Becky C. , Arnold Steven E.
Published: December 2022

Background

Normal Pressure Hydrocephalus (NPH) is a neurological condition where there is enlarged ventricular size with normal opening pressure at lumbar puncture. Etiology is uncertain but it is presumed to occur from an imbalance in the production and/or absorption of cerebrospinal fluid (CSF) leading to expansion of the ventricles. Clinical features include gait dysfunction, cognitive impairments, bladder incontinence. Diagnosis is challenging, given a large overlap in clinical and neuroradiological features and co‐morbidity with other more common diseases of aging, especially Alzheimer’s disease (AD) and Lewy body diseases. CSF amyloid and tau biomarkers can be helpful to identify AD pathology but do not exclude concurrent NPH. Currently, there are no biofluid biomarkers to assist in diagnosis of NPH. Here we describe a proteomic discovery pilot to identify candidate protein biomarkers associated with NPH.

Method

176 banked CSF samples from the MassGeneral Institute for Neurodegenerative Disease biorepository were separated into three groups: NPH (n=30), AD (n=65), and cognitively unimpaired neurological controls (CU‐N; n=81). Diagnoses were established based on comprehensive chart review and CSF AD biomarkers. For proteomic analysis, samples were prepared in batches and analyzed by LC‐MS/MS on an Orbitrap Fusion using a data‐independent acquisition method with non‐overlapping windows from 400‐1000 m/z. Batches were run sequentially, and raw files were searched per batch using Scaffold‐DIA and a custom data‐dependent generated library.

Result

Five proteins present in hemoglobulin (HBD and HBB), immunoglobulins (LV39 and KV105), and fibrinogen (FIBA) were increased in NPH compared to AD (Benjamini‐Hochberg adjusted p‐value pAdj <0.05). CSF erythrocyte counts were undetectable in all but one NPH subjects suggesting that a traumatic LP was not the cause of the increased levels. Two neuron associated proteins (VGF and NPTXR) were detected at lower levels in NPH compared to CU‐N subjects (pAdj<0.0001). Alpha‐1‐antichymotrypsin (AACT), was detected at high concentrations both in NPH and AD compared to CU‐N subjects (pAdj<0.02).

Conclusion

Proteomic analysis in NPH may identify novel pathological processes involved in the disease process and aid in the development of biomarkers in NPH.
Shared Decision‐Making in Dementia: A Scoping Review
Authors: Mattos Meghan K , Gibson Jessie , Jepson Laura , Ahn Soojung , Williams Ishan Canty
Published: December 2022

Background

Evidence supports that older adults with cognitive impairment can reliably communicate their values and choices, even as cognition declines. Shared decision‐making (SDM), including the patient, family members, and healthcare providers, is critical to patient‐centered care. The aim of this scoping review was to synthesize what is known about SDM in dementia.

Method

A scoping review was completed in PubMed, Ovid, and CINAHL. Keywords included content areas of dementia and shared decision‐making. Inclusion criteria were as follows: description of shared or cooperative decision making, cognitively impaired patient population, adult patient, and original research. Review articles were excluded, and those for which the formal healthcare provider was the only team member involved in the decision‐making (e.g., physician) and/or the patient sample was not cognitively impaired. Systematically extracted data were organized in tables, compared, and synthesized to identify what is known about SDM in dementia.

Result

The search yielded 263 non‐duplicate articles that were screened by title and abstract. Ninety‐three articles remained, and the full text was reviewed; 32 articles were eligible for this review. Studies were from across Europe (n = 23), North America (n = 7), and Australia (n = 2). The majority of the articles used a qualitative study design (qualitative only, n = 13; mixed‐method, n = 9), and 10 used a quantitative study design (intervention, n = 1; quasi‐experimental, n = 1; descriptive, n = 8). Categories of similar SDM topics emerged, including health promotion, end‐of‐life, advanced care planning, and housing decisions. The majority of articles focused on SDM regarding health promotion for the patient (n = 16). Topics related to health promotion included SDM in general patient care, activities of daily living, clinical appointments, fall prevention, diagnostic testing, and medications. Dementia diagnoses varied within studies and across the literature, ranging from mild cognitive impairment to late‐stage Alzheimer’s disease to dementia with Lewy bodies.

Conclusion

Findings illustrate that SDM requires deliberate effort and is preferred among family members, healthcare providers, and patients with dementia. Future research should include more robust efficacy testing of decision‐making tools, incorporation of evidence‐based SDM approaches based on cognitive status/diagnosis, and consideration of geographical/cultural differences in healthcare delivery systems.
A clinically relevant mouse model of the Trem2*R47H Alzheimer’s disease risk variant
Authors: Sasner Michael , Oblak Adrian L , Garceau Dylan , Kotredes Kevin P , Preuss Christoph , Uyar Asli , Pandey Ravi S , Lin Peter Bor‐Chian , Tsai Andy Po‐Yi , Carter Gregory W , Howell Gareth R , Lamb Bruce T ,   MODEL‐AD
Published: December 2022

Background

The TREM2 (triggering receptor expressed on myeloid cells 2) locus harbors numerous relatively rare variants associated with Alzheimer’s disease risk. The TREM2*R47H allele is one of the strongest genetic risk factors for developing late‐onset Alzheimer’s disease; patients exhibit both earlier onset of symptoms and rapid cognitive decline. TREM2 is expressed by microglia in the brain and plays a key role in modulating microglial activity. TREM2 expression is increased in AD and is associated with recruitment of microglia to amyloid plaques. An experimental model is therefore critical to study mechanisms of late‐onset AD, and the MODEL‐AD set out to create a clinically relevant mouse model.

Method

We used CRISPR to engineer the R47H variant into the mouse Trem2 locus; this model is available as JAX #27918. This model, as well as two other CRISPR‐generated Trem2*R47H models, display a splicing event seen in mice, but not humans, that leads to a novel splice form with a deletion of 119bp at the 5’ end of exon 2 (Xiang et al, Molecular Neurodegeneration, 2018). This leads to a decrease in ∼50% of both transcript and protein levels in brain homogenate in the mouse, indicating that the model expresses mutant Trem2 protein, but is also a hypomorph. To generate a more clinically relevant model, we have modified the existing Trem2*R47H mouse allele by using CRISPR to humanize the exon 2 splice site. Expression in these models was compared to normal Trem2 levels using both RNA‐seq and Western blot.

Result

The new model, which we are calling Trem2*R47HHSS for humanized splice site (JAX #33781), showed normal levels of expression. Relative to B6J controls, this new model expresses normal levels of each of the four transcripts. No truncated transcript was detected. Protein levels were restored to wild‐type levels in the model with the humanized splice site.

Conclusion

We expect that this model Trem2*R47H model will facilitate research into the mechanisms and pathways related to TREM2 genetic risk in late‐onset AD. For more information see www.model-ad.org.