bluuebunny/crossref_metadata_2025 huggingface dataset:
Unified Parkinson’s Disease Rating Scale (UPDRS) motor score subscale trajectories in Dementia with Lewy Bodies and Parkinson Disease Dementia in a community autopsy cohort
Authors: Choudhury Parichita , Zhang Nan , Adler Charles , Chen Kewei , Shill Holly , Shprecher David , Mehta Shyamal , Driver‐Dunckley Erika , Choi Alexander , Belden Christine , Goldfarb Danielle , Serrano Geidy E , Beach Thomas G , Atri Alireza
Published: December 2022

Background

We previously reported that in our autopsy‐confirmed cohort of Dementia with Lewy Bodies (DLB), Parkinson’s Disease Dementia (PDD) and Alzheimer’s Disease (AD), DLB with parkinsonism (DLB+Park) predicted faster progression of UPDRS‐III scores compared to PDD, DLB without parkinsonism (DLB‐Park), and AD. This study examined annualized rate of change of UPDRS‐III subscales in our cohort.

Methods

Data included were from participants in Arizona Study of Aging and Neurodegenerative Diseases (AZSAND) with clinicopathologic diagnosis of DLB (n = 48), PDD (n = 98) or pure AD (n = 48), and longitudinal movement exams. Mixed effects model (accounting for age, education, and sex) was used to determine predicted mean UPDRS‐III and subscale scores (0‐4) for all groups. Individual UPDRS‐III subscale scores were derived for: Body Bradykinesia, Limb Bradykinesia, Gait, Postural Instability, Limb Rest Tremor, Neck Rigidity and Limb Rigidity. Where applicable, scores for multiple limbs involved were averaged.

Results

Longitudinal data was analyzed for over 1430‐participant years. Parkinsonism was present in 65.6% of DLB participants. PDD participants were more likely to be treated with dopaminergic agents (87.8%) compared to (p<0.001) DLB+Park (57.6%), DLB‐park (0%) and AD (2.1%). Frequency (29.4% vs. 29.0%) and severity (mean±SE = 0.4±0.07 and 0.4±0.12) of Limb Rest Tremor was similar for PDD and DLB+park. Limb Bradykinesia frequency and severity were PDD: 100%, 2.4±0.11, DLB+Park: 96.8%, 2.1±0.18, DLB‐Park: 20%, 0.4±0.23, and AD: 62%, 1.1±0.16. Frequency of gait abnormality was 98.5% in PDD, 90.3% in DLB+park, 60% in DLB‐Park and 57.8% in AD. Rigidity was most frequent in the PDD group (88.2%), followed by DLB+Park (71%), AD (19.6%), and none DLB‐park (0%). Over 8 years trajectories for limb bradykinesia and gait were greater for DLB+park than PDD (Figure 1, Cohen’s d range 0.89‐2.18 and 0.63‐1.99 over 8 years, p<0.001).

Conclusion

Our results suggest that DLB+Park group have faster motor progression predominantly related to gait abnormalities and limb bradykinesia. Future analyses will explore more convergent data, integrated effects of various measures and their differential contributions in this cohort.
Differential responsiveness of outcome measures according to biomarker inclusion criteria: implications for trial design
Authors: Ottenhoff Lois , Vijverberg Everard G.B. , Prins Niels D. , Kroeze Lior A. , van Harten Argonde C. , van Berckel Bart NM , van der Flier Wiesje M. , Sikkes Sietske A.M. , Hendriksen Heleen M.A.
Published: December 2022

Background

Accurate selection of outcome measures, sensitive to the earliest cognitive changes, is essential to demonstrate treatment efficacy in secondary prevention trials in preclinical Alzheimer’s disease(AD). These outcome measures may differ according to biomarker inclusion criteria. We aimed to determine sensitivity to change over time, of commonly used cognitive measures.

Method

Participants with longitudinal neuropsychological assessments with available baseline biomarkers were included, from the SCIENCe project. We created different (overlapping) target groups based on inclusion criteria in pre‐clinical AD trials; (1)amyloid PET or CSF (A+, n = 114), (2)CSF p‐tau (T+, n = 124), (3)AT(N)+ (n = 41), (4)APoE4 carriers(E4+, n = 195) and (5)APoE4 carriers with amyloid(E4+A+,n = 65). As a control population, we included 150 controls with normal biomarkers. Linear mixed models, adjusting for age, sex and education, were used to investigate the sensitivity to change of 14 individual (standardized) neuropsychological tests and two composites with time as the variable of interest. Composites were based on Preclinical Alzheimer Cognitive Composite; PACC(1) and the Cognitive‐Functional Composite; CFC(2).

Result

A total of 556 participants where included(Age = 61.7±8.7, 44%F, follow‐up 3.1y ±2.7y)(Table 1). Linear mixed models in controls showed improvement over time in several tests, perhaps reflecting a learning effect: Stroop II/III, Wordlist Immediate Recall, Wordlist Delayed Recall and Letter Fluency. In contrast, all target groups showed significant decline in MMSE(Beta[‐0.09–0.26]), Digit‐Span‐Backwords (Beta[‐0.04‐ ‐0.06]), Trailmaking‐A (Beta[‐0.06–0.19]),‐B (Beta[‐0.15–0.29]), Stroop‐I (Beta[‐0.04–0.09]), Word‐List‐Recognition (Beta[‐0.09–0.16]) and Category‐Fluency (Beta[‐0.06–0.12])(Table 2). Linear mixed models showed a steeper decline on tests in AT(N)+ group. The composite measures showed significant decline in A+, AT(N)+ and E4+A+, (Beta[‐0.08–0.26]). With a sensitivity analyses we limited the follow up time to 2 years, leading to fewer neuropsychological tests showing decline and no decline in the composite measures.

Conclusion

We demonstrated that in preclinical AD, commonly‐used neuropsychological tests capture cognitive decline dependent on biomarker profiles. Tests for memory, attention and executive functioning were sensitive to decline, as were composite measures. When follow‐up time was limited to 2 years, fewer tests were sensitive to change including the composite measures. Therefore, careful selecting cognitive outcome measures and an appropriate period of time is important when defining the target population for the clinical trial.
Applying the German Version of the TOMMORROW Neuropsychological Assessment Battery for the diagnosis of Mild Cognitive Impairment in Clinical and Research Settings
Authors: Kunze Ursi , Welsh‐Bohmer Kathleen A. , Berres Manfred , Aebi Chantal , Monsch Andreas U.
Published: December 2022

Background

Among cognitively healthy participants, the TOMMORROW study (NCT01931566) aimed to identify those who went on to develop MCI due to AD over time (see Burns et al., 2021). Thus, based on the criteria of DSM‐5 and Albert et al. (2011) a battery of neuropsychological tests, i.e., TOMMORROW Neuropsychological Assessment battery (TOMM‐NAB) was compiled to assess cognition: memory (California Verbal Learning Test (CVLT‐II) long‐delay free recall, CVLT‐II short‐delay free recall, Brief Visuospatial Memory Test–Revised (BVMT‐R) delayed recall); executive function (Trail Making Test (TMT) B, digit span backward); language (semantic fluency (animals), lexical fluency (S‐, D, F‐words), Multilingual Naming Test (MiNT)); attention (TMT A, digit span forward) and visuospatial function (Clock Drawing Test (CDT), BVMT‐R copy). For the study subjects at the German‐speaking TOMMORROW study site, normative data were collected from 198 cognitively healthy individuals (see Romero et al., 2018). The goal of this study was to make the normative data of this excellent NAB available to clinicians and researchers in German‐speaking Europe.

Method

In order to provide clinicians and researchers with demographically‐corrected standard scores for all TOMM‐NAB variables, raw scores of the TOMM‐NAB were analyzed using the predicted sums of square (PRESS) statistics for variable selection and optimal nonlinear transformation to achieve normally distributed residuals. The following type of models were analyzed for each TOMM‐NAB variable: standard score = ((transformed) raw score ‐ predicted value) divided by residual standard error. The selection of terms was based on the PRESS ststistic (see Berres et al.2008 for details)

Result

The Figure provides an impression of the resulting TOMM‐NAB neurocognitive profile. Bars illustrate deviations from normal zero in terms of standard deviations.

Conclusion

The German version of the TOMM‐NAB can now be made available to clinicians and researchers and will allow for the best possible assessment with a set of sophisticated neuropsychological paper‐pencil tests.

Reference

Burns et al. Lancet Neurol 2021;20(7):537‐47. Albert et al. Alzheimers Dement 2011;7:270‐9. Romero et al. Alzheimers Dement 2018;4:314‐23. Berres et al. Statistics in Medicine 2008;27(10):1777‐90.
The eye as a biomarker for Alzheimer’s disease: oculomotor behaviours yield a novel digital biomarker for preclinical risk detection
Authors: Fernandez Gerardo , Mendez Luis , Lopera Francisco , Parra‐Rodriguez Mario A
Published: December 2022

Background

They eyes seem to hold a key to unveil early manifestations of Alzheimer’s disease (AD) pathology beyond retinal analysis. We have recently confirmed that eye‐tracking (ET) metrics recorded during performance on memory tasks can identify early and subtle changes in individuals at risk of or with AD dementia. There is a need for more robust and automatic classification methods that can provide affordable digital biomarker solutions for the preclinical detection of AD. This was the aim of this study.

Methods

A sample of 16 asymptomatic carriers (AC) of the mutation E280A‐PSEN1 from the widely investigated cohort of Antioquia, Colombia, and 55 healthy controls (HC) entered the study. Both groups were assessed with the novel Visual Short‐Term Memory Binding Task (VSTMBT) coupled with an ET device. The VSTMBT assesses the ability to temporarily hold bicoloured objects whose colours had to be remembered either as individual features (baseline) or integrated within unified representations (binding). Oculomotor behaviours (i.e., fixations, saccades, pupillometry) recorded using ET were subjected to Artificial Intelligence technology. This relied on Machine Learning classification using Lasso and Elastic‐Net Regularized Generalized Linear Models ("glmnet").

Results

AC and HC could not be distinguished based on traditional neuropsychological assessment (e.g., MMSE: HC = 29.7(0.4), AC = 29.5(0.8), p= 0.09). ML accuracy for classifying subjects into correct groups (HC and AC) was 98%. For a cut‐off of 0.72, 55 out of 55 HC and 14 out of 16 AC were correctly classified (see Fig 1).

Conclusion

Relative to behavioural measures (i.e., percentage correct recognition) drawn from the VSTMBT, AI‐powered technology can significantly enhance the detection of at risk individuals. By better characterising abnormal oculomotor behaviours, phenotypic features of the preclinical stages of AD can be unveiled. The facts that such a phenotypic expression characterised the majority of AC warrants further investigation in populations who hold less‐well known risk for AD.
Socioeconomic Deprivation, Genetics and Risk of Dementia
Authors: Klee Matthias , Leist Anja K , Veldsman Michele , Ranson Janice M , Llewellyn David J
Published: December 2022

Background

The risk of Alzheimer’s disease and other subtypes of dementia is determined by multiple pathways including genetic, environmental and lifestyle factors. With higher risk in socioeconomically deprived individuals, it remains unclear whether associations of genetic risk with dementia incidence may be modified by individual‐ or area‐level socioeconomic deprivation.

Method

Participants of the UK Biobank study attended baseline assessments at 22 assessment centers between 2006 and 2010 and were followed‐up until 2016 or 2017. Cox proportional‐hazards regressions with area‐level socioeconomic deprivation based on the Townsend Deprivation Index and individual‐level socioeconomic deprivation based on car and home ownership, housing type, and income were run. A comprehensive polygenic risk score was employed and potential mediation through lifestyle and depressive symptoms was assessed. In an imaging substudy, associations of socioeconomic deprivation with six imaging‐derived phenotypes including white matter hyperintensities were examined.

Result

196,368 participants (mean [standard deviation] age, 64.1 [2.9] years, 52.7% female) aged 60 years and older, of European ancestry, without dementia diagnosis or cognitive impairment at baseline were followed‐up for 1,545,316 person‐years (median [interquartile range] follow‐up, 8.0 [7.4‐8.6] years). In high genetic risk and high area‐level deprivation 1.71% (95% confidence interval, 1.44% to 2.01%) developed dementia compared to 0.56% (95% confidence interval, 0.48% to 0.65%) in low genetic risk and low‐to‐moderate area‐level deprivation (hazard ratio, 2.31; 95% confidence interval, 1.84 to 2.91). In high genetic risk and high individual‐level deprivation 1.78% (95% confidence interval, 1.50% to 2.09%) developed dementia compared to 0.31% (95% confidence interval, 0.20% to 0.45%) in low genetic risk and low individual‐level deprivation (hazard ratio, 4.06; 95% confidence interval, 2.63 to 6.26). There was no significant interaction between genetic risk and area‐level (P =.77) or individual‐level (P =.07) deprivation. An imaging substudy including 11,083 participants found greater burden of white matter hyperintensities associated with higher socioeconomic deprivation.

Conclusion

In older adults without dementia area‐level and individual‐level socioeconomic deprivation and genetic risk were significantly and independently associated with a higher risk of dementia. Dementia prevention interventions may be particularly effective if targeted to people living in deprived households and areas, regardless of genetic vulnerability.
Using 7T MRI to Evaluate COVID‐19 and Brain
Authors: Hosseini Akram A. , Bowtell Richard , Mougin Olivier , Penny Gowland , Katshu Mohammad Zia , Mukaetova‐Ladinska Elizabeta , Ibrahim Tamer , Girard Timothy D. , Vahidy Farhaan S. , Jacobs Heidi I.L. , Snyder Heather M. , de Erausquin Gabriel A. , Seshadri Sudha
Published: December 2022

Background

SARS‐CoV‐2 causes neurological, psychiatric and neurocognitive deficits in a large proportion of patients via direct or indirect viral invasion, systemic or intracranial inflammation, micro‐ or macrovascular pathologies, and hypoxic or systemic metabolic complications. The insult to brain function during the acute phase of COVID‐19 may accelerate neurodegenerative process and potentially increase the risk of Alzheimer’s Disease or Related Dementias. Ultrahigh Field (7T) MRI has an enhanced sensitivity and spatial resolution over and above clinical 3T MRI, allowing detection of small changes in brain sub‐structures and integrity.

Methods

The 7T COVID Consortium is an international collaboration across 5 sites which aims to study Ultrahigh Field neuroimaging correlates of clinical phenotypes, neuroimmunology, viral and host genetics, and neurodegenerative markers in a diverse, multi‐ethnic cohort of adults following SARS‐CoV2 infection. Multiple population cohorts include matched individuals following a clinically similar non‐COVID19 illness, and healthy controls including Framingham cohort and further comparative data from an independently‐funded genetically inherited Alzheimer’s disease. Synergized imaging sequences across the sites with Ultrahigh Field (7T) facilities, standardized bio‐sampling protocols, and adaptation of centralised REDCAP with WHO protocols and other studies within the COVID consortia1permit harmonised data analyses.

Results

Pilot data from the UK site, in Nottingham, included individuals who presented with neurological disorders associated with SARS‐CoV2 Alpha variant of concern (B.1.1.7). Clinical phenotypes and biochemical measures of patients during the acute phase of COVID‐19 were documented2and a prospective follow up for neurocognitive assessments and 7T MRI were arranged. Compared with healthy controls, hospitalised patients showed neuroimaging features of cerebral white matter hyperintensities suggestive of neurovascular ischaemia or neuroinflammation. These radiological cerebral white matter hyperintensities could progress 7 months after the acute illness despite clinical silence. Long COVID appeared to have increased susceptibility, that is suggestive of iron accumulation or inflammation, within the basal ganglia structures.

Conclusion

Pilot data suggest persistent or emergent neuroimaging abnormalities within a year after SARS‐CoV2 infection. Serial follow up may clarify long‐term impact of COVID‐19.

Funding: NIH/NIA, USA (R56AG074467), Nottingham Biomedical Research Centre (NIHR), Medical Research Council, UK (MR/T005580/1).

References:

1.de Erausquin, et al. http://doi.org/10.1002/alz.12255

2.Dhillon, et al. https://doi.org/10.3389/fneur.2021.640017
A Multimodal Genomic Analysis Framework Identifies Transposable Element (TE) Activation in Alzheimer's Disease
Authors: Feng Yayan , Hou Yuan , Pieper Andrew A. , Leverenz James B. , Cummings Jeffrey , Cheng Feixiong
Published: December 2022

Background

Transposable elements (TEs), known colloquially as “jumping genes” or “viral elements”, constitute approximately 45% of the human genome. Recent evidences showed that TEs are activated in AD by age‐associated epigenetic alterations or retroviral infection; yet, mechanisms of AD‐risk TE activation remain elusive.

Method

We investigated TE activation underlying AD pathobiology and therapeutic discovery using three large RNA‐sequencing datasets from the AD knowledge portal: (1) 284 AD patients and 150 healthy controls from Mount Sinai Brain Bank (MSBB), (2) 161 AD patients and 195 healthy controls from Mayo Clinic (Mayo), and (3) 106 AD patients and 44 healthy controls from Religious Orders Study or the Rush Memory and Aging Project (ROSMAP). We developed a multi‐modal genomic analysis framework that leverages TE differential expression, genome‐wide association study (GWAS), and X‐quantitative trait loci (X‐QTLs).

Result

We identified 6, 13, and 4 differentially expressed TEs (i.e., L1MC4, HERVK22‐int, and HERV1_LTRa) across MSBB, Mayo, and ROSMAP cohorts, respectively, at the family level. We further identified 442, 857, and 806 differentially expressed TEs (i.e., L1ME2) at locus levels across MSBB, Mayo, and ROSMAP cohorts, including 18, 5, and 2 locus‐based TEs in Mayo cohorts that specifically activated in neurons, microglia, and endothelial cells, respectively. Using integrative analysis of differentially expressed TEs with AD GWAS loci, and X‐QTLs, we identified the likely AD‐risk genes (including CEACAM19, CR1, and TOMM40, and cg04406254) involved in TE activation of AD. Using a drug repurposing approach, we showed that valacyclovir (an approved antiviral drug) was significantly associated with reduced incidence of AD in two large patient databases: (a) Hazard ratio (HR) = 0.55 (p < 0.001) in MarketScan with 7.32 individuals; and (b) HR = 0.72 (p < 0.001) in Optum with 5.62 million older individuals (> 65 years old). In addition, valacyclovir alters LINE‐1 expression in AD patient‐induced pluripotent stem cells (iPSC)‐derived neurons, supporting mechanistically potential beneficial effect of suppressing TE activation in AD.

Conclusion

This study characterized the genome regulatory control of AD‐risk TE activation and established the likely causal relationship between TE activation and AD pathobiology. The TE‐targeted therapeutic approaches (i.e., valacyclovir) will require randomized controlled trials.
Trajectories of Neurological Recovery 12 Months after Hospitalization for COVID‐19: A Prospective Longitudinal Study
Authors: Frontera Jennifer
Published: December 2022

Background

Little is known about trajectories of recovery 12‐months after hospitalization for severe COVID.

Method

We conducted a prospective, longitudinal cohort study of patients with and without neurological complications during index hospitalization for COVID‐19 from March 10, 2020‐May 20, 2020. Phone follow‐up batteries were performed at 6‐ and 12‐months post‐COVID symptom onset. The primary 12‐month outcome was the modified Rankin Scale (mRS) comparing patients with or without neurological complications using multivariable ordinal analysis. Secondary outcomes included: activities of daily living (Barthel Index), telephone Montreal Cognitive Assessment (t‐MoCA) and Neuro‐QoL batteries for anxiety, depression, fatigue and sleep. Changes in outcome scores from 6 to 12‐months were compared using non‐parametric paired‐samples sign test.

Result

Twelve‐month follow‐up was completed in N = 242 patients (median age 65, 64% male, 34% intubated during hospitalization) and N = 174 completed both 6‐ and 12‐month follow‐up. At 12‐months 197/227 (87%) had ≥1 abnormal metric: mRS>0 (75%), Barthel<100 (64%), t‐MoCA≤18 (50%), high anxiety (7%), depression (4%), fatigue (9%) and poor sleep (10%). 12‐month mRS scores did not differ significantly among those with (N = 113) or without (N = 129) neurological complications during hospitalization after adjusting for age, sex, race, pre‐COVID mRS and intubation status (adjusted OR 1.4, 95% CI0.8‐2.5), though those with neurological complications had higher fatigue scores (T‐score 47 vs 44, P = 0.037). Significant improvements in outcome trajectories from 6‐ to 12‐months were observed in t‐MoCA scores (56% improved, median difference 1 point, P = 0.002), and Neuro‐QoL anxiety scores (45% improved, P = 0.003). Non‐significant improvements occurred in fatigue, sleep and depression scores in 48%, 48% and 38% of patients, respectively. Barthel and mRS scores remained unchanged between 6 and 12‐months in >50% of patients.

Conclusion

At 12‐months post‐hospitalization for severe COVID, 87% of patients had ongoing abnormalities in functional, cognitive or Neuro‐QoL metrics and abnormal cognition persisted in 50% of patients without a prior history of dementia/cognitive abnormality. Only fatigue severity differed significantly between patients with or without neurological complications during index hospitalization. However, significant improvements in cognitive (t‐MoCA) and anxiety (Neuro‐QoL) scores occurred in 56% and 45% of patients, respectively, between 6‐ to 12‐months. These results may not be generalizable to those with mild/moderate COVID.
Predicting Major Decline in Older Adults: The Role of Time Spent Out of Home
Authors: Au‐Yeung Wan‐Tai M. , Miller Lyndsey M. , Steele Joel S. , Mattek Nora , Beattie Zachary T , Silbert Lisa C , Kaye Jeffrey A
Published: December 2022

Background

For older adults in community settings, predicting undesired outcomes (needing higher levels of care or death) is important for advancing preventative care and achieving successful aging. We examined whether a combination of baseline characteristics (demographic, clinical) and a continuous digital measure of general mobility and socialization (time‐out‐of‐home) would be predictive of transitions of care and mortality.

Method

Longitudinal data from community‐dwelling older adults in the Collaborative Aging Research using Technology (CART) Study was examined for occurrences of undesired life transitions: moving residences due to needing more assistance, receiving non‐temporary in‐home assistance, and death. In‐home sensor data (passive infrared motion and contact sensors) was used to create an algorithm for time when no one was home (TOH). For homes with a transition recorded, a 90‐day window preceding the transition was used to calculate average TOH per day; for homes that did not have transitions, a 90‐day window was randomly selected. Logistic regression was used to predict whether mean duration of TOH (hours), age, gender, Clinical Dementia Rating Scale Sum of Boxes (CDR‐SOB), and Cumulative Illness Rating Scale (CIRS) could predict undesired transitions in single‐resident and dual‐resident homes of older adults.

Result

177 participants residing in 123 homes were included in the analysis: 56.1% of the homes were single‐resident homes. Mean age in years was 72 (6.4), 52% of participants were women, mean CDR‐SOB = 0.30 (0.46), and mean CIRS = 22 (3.9). Transition to needing greater assistance or death was significantly associated with less TOH (OR 0.66 [95% CI 0.44‐0.98]) after controlling for known risk factors that included age, CIRS, CDR‐SOB and gender. Older age (OR=1.07 [CI 0.98‐1.16]), higher CDR‐SOB (OR=2.66 [CI 0.80‐8.87]), higher CIRS (OR=1.05 [CI 0.90‐1.21]), and being male (OR=0.55 [CI 0.19‐1.64]) were associated with a major transition or death with wide CI’s among these mediating factors.

Conclusion

Less duration of TOH (likely reflecting mobility and motivation) is predictive of major decline in older adults after controlling for known demographic and clinical risk factors. Digital behavioral biomarkers assessing older adults’ day‐to‐day behaviors may provide valuable information in addition to clinical assessments.
Mechanisms Mediating the Anti‐inflammatory Effects of Eicosapentaenoic Acid in the APPswePS1dE9 Alzheimer's Mouse Model
Authors: Yavari Mahsa , Ramalingam Latha , Harris Breanna N. , Kahathuduwa Chanaka , Zu Yujiao , Chavira Angela , Biltz Caroline , Alers Kaylee , Mounce Philip , Moustaid‐Moussa Naima
Published: December 2022

Background

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder characterized by amyloid‐beta (Aβ) plaques, which may be exacerbated by obesity. We previously reported anti‐obesity and anti‐inflammatory effects of eicosapentaenoic acid (EPA), in diet‐induced obese mice. Therefore, the objective of this research is to determine whether EPA also protects against AD‐associated Aβ deposition.

Method

Male and female AD mouse model APPswePS1E9 transgenic (TG) and non‐TG wild type littermates (WT) were fed with low fat (LF), high fat (HF), or HF supplemented with 36g/kg EPA (EPA) for 8 months. Mice were metabolically phenotyped during the intervention and blood and tissues were collected at the end of the study. Cortex RNA was isolated, and changes in genes related to AD, obesity, and inflammation were measured. Data were analyzed by 3‐way ANOVA using GraphPad Prism.

Result

HF groups weighed significantly more than LF groups (p < 0.001), but other groups were comparable regardless of diet or genotype but overall, males weighed more than females. TG mice had higher serum Aβ‐40 levels than WT mice (p= 0.004), paralleled with higher cortex human APP mRNA levels in TG mice (p = 0.0204). Compared to HF, EPA decreased serum Aβ‐40 in WT male mice (p = 0.0182) as well as APP gene expression in the cortex of male and female TG mice (p = 0.0168 and 0.0030). Moreover, TG mice expressed higher level of MCP1 and IL1β (p = 0.0158 and 0.0142, respectively) mRNA levels compared to WT. Females in both genotypes expressed higher level of MCP1, IL1β and NLRP3 than males (p = 0.0025, 0.0038, and < 0.0001 respectively). In addition, EPA exhibited anti‐inflammatory effects in both sexes of TG mice as indicated by downregulation of mRNAs levels for MCP1 (p = 0.0226 and 0.0108) NLRP3 (p = 0.0205 and < 0.0001) and for IL1β in TG females only (p= 0.0344).

Conclusion

Our data indicate protective effects of EPA in AD, in part, by reducing Aβ deposition, possibly through inflammatory/neuroinflammatory mechanisms. Given the popularity of fish oil supplements, our findings merit further investigation to dissect mechanisms of fish oil effects especially in AD patients with obesity.
Identifying Matrix‐ and Transporter‐Type Pericytes in Human Brain
Authors: Khan Sofia M , Bauman Allison J. , Elkadi Osama , Nelson Amy R.
Published: December 2022

Background

Pericytes are vascular mural cells that wrap around capillaries and are crucial for the formation and maintenance of the blood‐brain barrier (BBB). A recent RNAseq study discovered that the human brain has two novel and distinct pericyte subtypes (Yang et al., 2022). The first, termed transporter (T)‐type, are enriched with transporter genes. The second are matrix (M)‐type pericytes which have increased expression of extracellular matrix (ECM) genes. Notably, the authors found that a decrease in M‐type pericytes and not T‐type pericytes contributes to the formation of Alzheimer’s Disease (AD). The loss of M‐type pericytes is speculated to lead to perturbations of vascular ECM. Here, we aimed to determine which protein markers work best for the identification of M‐ and T‐type pericytes and their localization in human hippocampal and cortical post‐mortem brain tissues.

Method

Based on the Yang et. al. paper, we selected COL4A1 and GAT1 to identify M‐pericytes and T‐pericytes, respectively. Next, we used immunofluorescence staining and microscopy to study the localization of these pericyte types in post‐mortem human brain tissue. Primary antibodies (mouse‐COL4A1 and goat‐GAT1) were incubated in blocking buffer on the tissue sections at room temperature overnight. The next day, the sections were washed in phosphate buffered saline (PBS) and incubated in secondary antibodies (anti‐mouse, anti‐goat, and UEA) for 90 minutes and subsequently washed with PBS. The sections were treated with an autofluorescence quenching treatment (5min) and then cover slipped and imaged.

Result

We successfully performed immunofluorescence staining to identify M‐ and T‐type pericytes in human hippocampus and cortex. We are currently working to quantify M‐ and T‐type pericyte number and coverage in human hippocampus and cortex.

Conclusion

Knowing how to identify these new pericyte types in human brain is essential to begin understanding their abundance, location, and possible functions. In the future, we will measure changes in M‐ and T‐type pericytes in AD vs. aged‐matched control post‐mortem brain tissues using our immunofluorescence protocol.
p75NTR modulation counteracts alterations in neuronal and glial activity‐dependent profiles of gene co‐expression networks in tauopathy mice
Authors: Latif‐Hernandez Amira , Moran‐Losada Patricia , Yang Tao , III Robert R. Butler , Tran Kevin C , Liu Harry , Massa Stephen M. , Wyss‐Coray Tony , Longo Frank M.
Published: December 2022

Background

P75NTR is a key mediator in the regulation of neuronal plasticity, and modulation of its signaling prevents synaptic dysfunction in Tau.P301S mice, as measured by long‐term potentiation (LTP). Since LTP alters gene expression programs and results in transient post‐translational modifications at synapses, we asked whether tauopathy‐associated alterations in gene co‐expression, in response to stimulation, can be counteracted by p75NTR modulation.

Method

LM11A‐31 (C31), a small molecule p75NTR modulator, was orally administered to Wildtype (WT) and Tau.P301S mice for 3 months, at a time when tau pathology was fully developed. RNA sequencing with cell‐type enrichment analysis was performed on unstimulated and stimulated hippocampal slices that underwent theta burst stimulation (TBS) to induce late‐phase LTP and generate activity‐dependent profiles of gene co‐expression networks, using weighted analysis with a soft‐threshold power of 18 to achieve scale‐free topology R2>0.8 and module size 25.

Result

The most significantly expressed activity‐dependent transcriptional co‐expression modules related to synaptic function in WT mice, that were down‐regulated in Tau.P301S mice, showed an enrichment for genes in neurons and transcripts selectively expressed in CA1 pyramidal cells. The top significant gene pathways enriched in these modules were glutamatergic synapse, post‐synapse, pre‐synapse, post‐synaptic density, dendritic and neuron spine, with Cacna1h, Gabbr1, Kalrn, Shisa7, and Epha7. All of these were normalized to WT levels with C31 treatment. In addition, significantly up‐regulated co‐expression modules in Tau.P301S relative to WT mice associated with pathways such as complement binding, immune system process, myeloid leukocyte migration and neutrophil chemotaxis were enriched in genes found in microglia, such as Trem2, C1qa, C1qb, C1qc, Tyrobp. Notably, these expression profiles also reverted to WT levels with C31. Further, comparison of mouse and human modules demonstrated that those affected in treated mice have similar up‐ and down‐regulated patterns of expression as those found in human AD.

Conclusion

Modulation of p75NTR with C31 normalized tauopathy‐related neuronal and glial transcriptional profiles. These transcriptional alterations are in part concordant with alterations found in human AD‐relevant gene co‐expression networks.
Rater perspectives on Applied Training of cognitive Clinical Outcome Assessment (COA) scales delivered by neuropsychology experts
Authors: Wacker Svenja Mirjam , Barbone Jordan Mark
Published: December 2022

Background

Cognitive assessments are critical in understanding the effects of investigational therapies, but their use can be vulnerable to variability test administration and scoring. Careful training of raters on proper test administration cognitive tests is crucial to ensure optimal reliability and validity of clinical outcome data (Targum, 2006) and (Jeglic, 2007). Trainee feedback is important in ensuring a training program is comprehensive, well‐delivered and well‐received.

Method

Perceived effectiveness of live training videoconferences, with expert neuropsychologists as clinical coaches (referred to as Local Expert Advisors “LEADs”), was evaluated via optional, online “Rater Training Survey” deployed to raters to report on their training experience, trainer, and preparedness for live assessments with study participants.

Result

Of 261 survey invitations, 48 (18.4%) raters submitted responses on training sessions with 6 different expert trainers, questions on LEAD Knowledge, LEAD Feedback, and Rater Equipped received 100% positive responses. Additional comments lauded the trainers’ engaging and constructive approach to training delivery with effective preparation for assessments with study subjects.

Conclusion

This survey format proved to be a low‐burden approach to quality control of clinical coaches. Raters, trained through this rater training program, reported an overwhelmingly positive training experience with the program overall and with the Applied Training session, specifically. The “personal touch” of live training modalities with expert coaches appears to be an effective training approach for raters’ skill mastery and feeling of preparedness.
Impact of Phospholipase C Gamma 2 Alzheimer's Disease Variants on Microglial Biology and Disease Pathogenesis
Authors: Tsai Andy Po‐Yi , Lin Peter Bor‐Chian , Dong Chuanpeng , Prisco Gonzalo Viana Di , Wang Nian , Bissel Stephanie J , Oblak Adrian L , Moutinho Miguel , Liu Yunlong , Atwood Brady , Nho Kwangsik , Lamb Bruce T , Landreth Gary E
Published: December 2022

Background

Alzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Phospholipase C gamma 2 (PLCG2), whose variants confer altered risk for AD, is a critical signaling element for various immune receptors and is a key regulatory hub gene for immune signaling. A functional hypermorphic P522R variant (rs72824905) of PLCG2 has been identified to be protective against AD (OR= 0.68, p=5.83‐10). Significantly, we identified a novel SNP (rs617749044) associated with elevated AD risk (OR=1.164; p=0.047) encoding the PLCG2 M28L variant.

Method

To investigate the impact of PLCG2 AD risk variants on microglial biology and disease pathogenesis, we have generated mice bearing either the M28L risk or the P522R protective PLCG2 variant, all crossed onto the 5XFAD amyloidogenic murine model of AD.

Result

Here, we provide comprehensive analysis of PLCG2 action in mouse models of AD. We demonstrate that PLCG2 variants regulate protein‐protein interaction, alter microglial phenotypes in 5XFAD mice, regulate cytokine levels, drive distinct transcriptional phenotypes of microglia, and affect plaque pathology. Our data demonstrate that the M28L variant results in accelerated and exacerbated disease‐related pathology, and conversely, the P522R variant appeared to attenuate disease severity and progression.

Conclusion

Together, our finding provides evidence that PLCG2 play an important role in AD pathophysiology, indicating PLCG2 as a potential new therapeutic target for AD.
Association of Cerebrovascular Reactivity and Cognitive Performance in a Racially Diverse Cohort
Authors: Kulshreshtha Ambar , Henley Brandon , Okafor Maureen , Rogers Steven , Thomas Tiffany , Goldstein Felicia C , Hajjar Ihab
Published: December 2022

Background

Cerebrovascular reactivity (CVR) to increased carbon dioxide (CO2) reflects cerebral microvascular function and is impaired in hypertension and stroke. Limited studies have looked at its relationship with cognitive performance in African Americans and Whites.

Methods

We used data from the Brain‐Stress Hypertension and Aging Program cohort (B‐SHARP) consisting of racially diverse individuals with normal cognition or mild cognitive impairment (MCI). CVR was measured using advanced signal modeling approach developed by BH/IH during blood oxygenation level dependent (BOLD) resting state ‐fMRI. Participants underwent cognitive assessment using global and domain‐specific tests such as Montreal Cognitive Assessment (MoCA), Boston Naming Test (BNT), Hopkins Verbal Learning Test‐Revised (HVLT‐R), and Trail Making Test. We used multivariate regression models to assess the relationship of CVR and cognitive domains and tested interaction of CVR with race.

Results

Successful CVR data were completed on 219 participants with mean age= 65.3 years (SD 7.8), 46% African American and 65% women. An increased resting whole brain CVR was associated with a higher MoCA score (β = 6.46, SE 2.43, p‐value 0.008), higher BNT score (β =2.15, SE 0.93 p‐value 0.02), and shorter time on Trail B‐A, (β= ‐113.4, SE 42.0, p‐value 0.007) after adjusting for mean arterial pressure. After adjusting for age, sex, and race, increased resting whole brain CVR was associated with higher MoCA (β =4.4, SE 2.26, p‐value 0.05), BNT score (β =1.46, SE 0.89, p‐value 0.1) and Trail B‐A score (β =‐86.7, SE 40.3, p‐value 0.03). There was no association with delayed memory based on HVLT‐R. The results were similar for individuals with normal cognition or MCI. There was a significant interaction by race (p<0.01) such that whole brain CVR was associated with better performance on all cognitive tests for African Americans but not for Whites.

Conclusions

Higher CVR, reflected by resting state BOLD‐fMRI, was associated with higher overall cognitive status and specific domains including language and executive functioning in individuals with normal cognition or MCI. The differential effect in African Americans vs Whites could suggest a greater contribution of microvascular dysfunction for the higher prevalence of cognitive impairment in African Americans.
Dissecting the Neuropathological Contributors to Rapidly Progressive Dementia
Authors: Day Gregory S , Lazar Evelyn , Ghayal Nikhil B , Roemer Shanu F , Graff‐Radford Neill R. , Dickson Dennis W.
Published: December 2022

Background

Most series exploring the causes of rapidly progressive dementia (RPD) rely on clinical diagnoses, with limited pathological confirmation. This approach may underestimate the contributions of Alzheimer disease and related dementias to RPD, recognizing challenges associated with extrapolating clinical phenotypes to neuropathological diagnoses. A clearer understanding of the neuropathological causes of RPD is needed to inform the diagnosis and treatment of patients. To meet this need, we determined the neuropathological causes of RPD within the Mayo Clinic neurodegenerative brain bank.

Method

Patients with disease duration <4.0 years (symptom‐onset to death due to dementia) were identified within the Mayo Clinic neurodegenerative brain bank (1998‐2020). Available clinical records were reviewed, and details extracted including demographics, family history, dominant symptoms/signs at onset, and common comorbidities (depression, psychoses, sleep disturbance). Neuropathological diagnoses were assigned following standard protocols.

Result

310/8586 (3.6%) cases met RPD criteria. Relative to typically progressive cases, prion disease most commonly presented as RPD (74%, 32/43), followed by progressive supranuclear palsy/corticobasal degeneration (PSP/CBD: 7.5%, 142/1894), other frontotemporal lobar degeneration (FTLD: 5.7%, 32/561), Lewy body disease (LBD: 4.1%, 49/1202), and Alzheimer disease (AD: 1.8%, 48/2687). Average age‐at‐symptom onset was 69.5±10.4 years. Patients with rapidly progressive AD were older than others (p<0.01), except LBD. Patients with FTLD were younger than others (p<0.05), except prion disease. Average disease duration was 2.9±1.0 years: prion diseases had the most rapid disease course (1.6±1.3 years). Comorbid cerebrovascular disease (25.5%), and clinically symptomatic depression (41.3%), psychoses (37.1%) and sleep disturbances (39.4%) were common across groups. Only psychosis was associated with shorter disease duration (β=‐0.31 years, CI95% [‐0.53, ‐0.082]; controlling for age‐at‐symptom onset).

Conclusion

Rapidly progressive neurodegenerative diseases accounted for 3.6% of cases in this neurodegenerative brain bank. Although prion disease commonly presented as RPD, atypical presentations of more prevalent neurodegenerative diseases accounted for most cases. Atypical (rapidly progressive) variants of typical neurodegenerative diseases warrant consideration in clinical practice.
Administration of Selective α2‐Adrenergic Receptor Agonist Dexmedetomidine During Spine Surgery is Associated with Reduced Postoperative Increase in Plasma p‐Tau181
Authors: Wilson Edward N. , Pinkert Vincent J , Navales Andres Tirado , Quinn Joseph F , Schenning Katie J
Published: December 2022

Background

Recent studies have revealed that biomarkers of neuronal injury and Alzheimer's disease (AD) are increased in patients following major surgery. However, the contribution of specific anesthetic agents, such as inhalational or intravenous, remains unclear. In this study, we evaluated whether patients having a predominantly inhalational anesthetic (GAS) compared to patients having a predominantly intravenous anesthetic (IV) would have differences in plasma p‐tau181 levels from preoperative baseline to 3‐months postoperatively. We also examined whether there were differences in p‐tau181 in patients who were intraoperatively administered dexmedetomidine, a selective α2‐adrenergic receptor agonist with neuroprotective effects.

Method

In this prospective observational study of 70 patients (>= 65 years) having elective inpatient spine surgery under general anesthesia at a single academic center, we compared changes in plasma p‐tau181 levels from preoperative baseline to 3‐months postop in patients who received GAS (n=38) compared to IV (n=32). Plasma p‐tau181 levels were measured using the fully automated immunoassay analyzer (Lumipulse G1200, Fujirebio). T‐tests were used to compare 2 groups and 2‐way ANOVA with Tukey's multiple comparisons test was used for dexmedetomidine analyses.

Result

On average plasma p‐tau181 levels increased in the GAS group (n=38) and decreased in the IV group (n=32, mean ± SD; 0.64 ± 2.46 pg/mL vs. ‐1.06 ± 3.24 pg/mL; p=0.014) at 3‐months postop. This was despite the IV group having increased duration of surgery, blood loss, and hospital length of stay. A greater postop increase in plasma p‐tau181 was observed in patients not administered dexmedetomidine (p=0.002). Patients who were not administered dexmedetomidine had a greater increase in postop plasma p‐tau181 in both the GAS and IV groups (main effect of Dexmedetomidine, p=0.02).

Conclusion

Changes in plasma p‐tau181 levels from preoperative baseline to 3‐months postop were greater in older surgical patients who had GAS compared to IV maintenance of general anesthesia. Importantly, patients not receiving dexmedetomidine showed a greater increase in plasma p‐tau181 levels regardless of anesthesia type.
Case‐control co‐twin study on the associations of dementia risk factors with episodic memory in nonagenarians
Authors: Varjonen Anni , Schwarz Claudia , Kaprio Jaakko , Vuoksimaa Eero
Published: December 2022

Background

Several risk and protective factors of dementia are known, but the importance of genetic and environmental influences and the antecedents of cognitive functioning in 90‐year‐olds are not well known. Genetic and environmental confounding can be controlled better by using family data compared to samples of unrelated individuals. We examined dementia risk factors in 90‐year‐olds by conducting a case‐control co‐twin study on the associations of physical and psychological well‐being with episodic memory (EM).

Method

We invited 90‐year‐old twins from a population‐based older Finnish Twin Cohort study to participate in the ongoing NONAGINTA –study that includes questionnaires (risk factors) and telephone interview (cognitive functioning). To date, eight full same‐sex pairs have cognitive data available (6 female, 6 monozygotic). We calculated a risk score for each twin and co‐twin, based on the following factors: depressive symptoms (measured with the Center for Epidemiological Studies – Depression, CES‐D), body mass index (BMI), physical activity (MET hours), life satisfaction, neuroticism, and years of education. Within each twin pair, co‐twins were assigned as having greater versus lower risk score. We ran a paired t‐test to compare EM performance (total number of recalled words in three trials of 10‐word list) in co‐twins with greater versus lower risk score. Associations of individual factors with EM were studied with exact McNemar test.

Result

Mean difference in EM within twin pairs was 3.38 (SD = 2.50). Pairwise correlation of EM was r = 0.75 and seven twin pairs were discordant for EM. Co‐twins with lower risk score remembered more words (M = 13.25, SD = 5.59) than their co‐twins with greater risk score (M = 12.88, SD = 5.82), but this difference was not significant (p = 0.82). Examining each risk factor individually, the strongest – non‐significant – association was that co‐twins with greater life satisfaction had better EM in 5/6 pairs (p = 0.10).

Conclusion

Preliminary data did not indicate any significant within‐twin pair associations of dementia risk and episodic memory. As expected, co‐twins were highly similar in EM. Ongoing data collection will result in more twin pairs and greater statistical power to see if the suggestive association of greater life satisfaction (or other factors) with better EM is evident in nonagenarians.