bluuebunny/crossref_metadata_2025 huggingface dataset:
Computer‐administered neuropsychological assessment batteries: Validity, reliability, and user experience in an Australian sample of community‐living older adults in the CogSCAN Study
Authors: Kochan Nicole A. , Croot Karen , Crawford John D. , Allison Karen C , Rossie Matilda , Brodaty Henry , Lam Ben C. P. , Henry Julie D , Lee Teresa , Draper Brian , Close Jacqueline , Ong Min Yee , Bentvelzen Adam , Sachdev Perminder S.
Published: December 2022

Background

Access to a “gold‐standard” in‐person neuropsychological assessment to detect cognitive decline in older adults using paper‐and‐pencil (PnP) tests is limited. Computerized neuropsychological assessments (CNAs) potentially provide lower cost, scalable, accessible alternatives but critical psychometric data on the validity, reliability and user‐experience of CNAs in older adults are lacking.

Method

263 community‐dwelling individuals aged 60 years and older without dementia were assigned to complete two CNA batteries and one standardised neuropsychological assessment with 14 PnP tests, one week apart (Construct Validity Group) or two CNAs on two occasions, one month apart (Reliability Group). CNAs were self‐administered under supervision. Orders of CNA batteries, and of CNA and PnP sessions were counterbalanced (Figure 1). Participants completed questionnaires evaluating their experience after each CNA battery. Four CNA batteries were investigated: Cambridge Brain Sciences (CBS), CANTAB, Cogstate, and NIH Toolbox, each containing 5—8 tests; key variables recommended by the test developers were examined (Table 1).

Result

Participant characteristics are summarised in Table 2. Concurrent Validity: Modest correlations (r’s of 0.3‐0.6) between CNA and PnP measures were observed for all CNA batteries, generally aligning with corresponding domains, though notably reflecting the multidimensionality of cognitive measures (Table 3); the strongest associations (r ≥0.5) were with attention and processing speed measures across three CNA batteries, also NIH Toolbox vocabulary, memory and executive measures.

Reliability: One‐month test‐retest reliabilities of individual measures were variable (Table 4); across three batteries some, typically speed measures, had reliability coefficients ≥ 0.7.

User Experience: Completion rates were high (96‐100%). Usability ratings of CNAs were high on average, although variability was large for CBS (Figure 2). Ratings of acceptability were lower than usability, though on average, participants endorsed CNAs positively.

Conclusion

A selection of computerized measures demonstrated adequate psychometric standards for concurrent validity with ‘gold standard’ in‐person neuropsychological assessments, alongside good usability and acceptability, though test‐retest reliability was low for many measures. CogSCAN’s comprehensive comparative data will guide researchers in selecting the most suitable CNA measures for older adults. Work in progress is investigating CNA validity, reliability and user experience in older adults with cognitive decline and culturally and linguistically diverse older adults.
Assessing synaptic integrity in Alzheimer’s brain with UCB‐J
Authors: Kumar Amit , Nordberg Agneta K
Published: December 2022

Background

Synaptic loss is an eminent feature of Alzheimer’s disease (AD). Synapses critical for neuronal transmission are regulated by synaptic vesicles (SV), which expresses an integral transmembrane protein called SV protein 2A (SV2A) throughout the brain. Notably, reduced SV2A expression has been implicated in AD and other proteinopathies. UCB‐J is a recently developed PET‐tracer, which target SV2A, to study synaptic integrity in different neurological disorders. Though several UCB‐J in vivo PET studies have been published in AD, there have been some discrepancies between the findings. Many of these studies indicated potential correlations between tau deposition, atrophy, cognitive‐impairment, and loss of UCB‐J binding. Based on these in vivo observations, we found it of utmost relevance to perform extensive pre‐clinical validation of UCB‐J in AD brains with postmortem brain imaging techniques.

Method

We performed radioligand binding assays (saturation and competition) alongside large brain section autoradiography in AD and control brains.

Result

3H‐UCB‐J competition studies with unlabelled‐UCB‐J showed one‐binding site (IC50: ∼ 10 nM) in the frontal cortex (FC) of AD and control brains. Saturation studies in FC region of AD and control brains showed much higher specific binding in synaptosomal membrane P2‐fraction (Bmax: 5.8 ‐ 8.7 pmol/mg, Kd ∼ 5.0 nM) as compared to brain homogenates (Bmax: 0.09 ‐ 0.18 pmol/mg, Kd ∼ 4.0 nM). P2‐fraction saturation binding study clearly highlighted the loss of UCB‐J binding in FC of AD brain as compared to control brain. In contrast, large brain hemisphere section autoradiography incubated with 3H‐UCB‐J showed unexpectedly higher regional binding in AD brain sections as compared to control, motivating further mechanistic pre‐clinical validation with other synaptic markers in AD and other proteinopathies.

Conclusion

Our findings explicitly demonstrated high specificity of UCB‐J for SV2A in AD and control brains. UCB‐J specific binding was much higher in P2‐fraction than brain homogenate (P2‐fraction > brain homogenate) and highlighted the expected loss of UCB‐J binding in AD brain. Competition and saturation binding studies complemented each other and showed only one‐binding site with nM‐affinity in AD and control brains. Unanticipated high UCB‐J binding in AD brain in autoradiography studies indicate potential interaction with other brain tissue component, warrant further investigation.
Do the extracellular vesicles excreted during neuronal cell death play a neuron‐glia signalling role in neurodegeneration.
Authors: Barnard Jodi Louise
Published: December 2022

Background

During neurodegeneration, dying neuronal cells may trigger neuroinflammatory responses or inform neighbouring glial cells of their dying status by releasing extracellular vesicles. Karyoptosis is a novel cell death caused by a block in autophagy which was first discovered in a dentatorubral‐pallidoluysian atrophy (DRPLA) mouse model. During karyoptosis cells exhibit signs of nucleophagy (nuclear breakdown) and vesicle expulsion. Understanding the molecular underpinnings of neurodegeneration is important for informing possible therapeutic intervention. Our hypothesis is that dying neurons release vesicles which are phagocytosed by microglia, and this leads to an inflammatory response.

Method

Using ex vivo samples from the DRPLA mouse model, immunofluorescence, and confocal imaging, we studied the phenotype of microglia pathologically. We used disease‐relevant brain regions with high levels of karyoptosis, such as the dentate nucleus. To further understand the microglial response and visualise the likely phagocytosis of these vesicles, we are also using a human neuroblastoma cell line to induce karyoptosis and purify the released vesicles for application to cultured BV2 microglia‐like cells.

Result

Our initial data shows that more microglia are present in pathological areas with high karyoptosis activity in the DRPLA mice. Analysis of these microglia revealed an increased cell soma size, decreased branch length, and decreased intersections per microglia in the DRPLA model, all of which suggest the increased activation and de‐ramification of microglia in DRPLA mice.

Conclusion

These findings indicate differences in the total number, activity, and overall phenotype of microglia in areas with high karyoptosis in this DRPLA model. This suggests that the vesicles released during this cell death process may be influencing microglia. Future work will focus on replicating these findings in vitro. Extracellular vesicles collected from human neuroblastoma will be applied to cultured microglia to visualise the uptake of vesicles, decode their contents, and further characterise any microglial response. This work will help further the understanding of how neuron‐glia signalling contributes to neurodegeneration.
C‐reactive protein (CRP) blood concentrations associate with reduced global system segregation in middle‐aged individuals
Authors: Bartrés‐Faz David , Wang Yunpeng , Cabello‐Toscano María , Cattaneo Gabriele , Solé‐Padullés Cristina , Vaqué‐Alcázar Lídia , Mulet‐Pons Lídia , Sánchez Javier Solana , Tormos‐Muñoz Josep Mª , Drevon Christian A , Gundersen Thomas , Fjell Anders M , Walhovd Kristine B
Published: December 2022

Background

High concentrations of circulating C‐reactive protein (CRP) have been related to poorer cognition in adults (Lewis et al. Age Ageing. 2021;50:2199). Within the Lifebrain consortium (Walhovd et al. Eur Psychiatry. 2018;50:47), we recently reported overall lifespan associations between increased CRP and smaller hippocampal (HPC) volumes, albeit these could not be observed in one subsample of middle‐aged individuals (Wang et al. Brain Behav Immun. 2022;100:243). Here we hypothesized that functional brain integrity measures would be sensitive to predict CRP levels in this group. We focused on global system segregation (SyS) a graph theory‐based metric which quantifies the extent to which major functional networks are segregated from each other.

Method

We included 336 volunteers (mean age 53.8; SD: 7.1; 47.9% women) from the Barcelona Brain Health Initiative (Cattaneo et al. Front Aging Neurosci. 2018;10:321). High‐sensitive CRP (hsCRP) concentrations were determined through dry blood samples and log10 transformed (Wang et al. Brain Behav Immun. 2022;100:243). Adjusted HPC volumes were estimated from T1‐wheigthed 3T MRI acquisitions (Raz et al. Cereb Cortex 2005;15:1676). SyS values were calculated (Ewers et al. Brain. 2021;144:2176) from 100 nodes defined by the Schaefer‐Yeo atlas (Fig 1a). Multiple linear regression investigated the associations between age, gender, cognitive function (MMSE and episodic memory), HPC volumes, APOE status and SyS as predictor variables and hs‐CRP as the dependent measure.

Result

In the adjusted model only SyS (β= ‐0.56, p<0.05) and APOE (β= ‐0.21, p=0.003) predicted hsCRP concentrations. Global SyS was negatively related to hsCRP (Fig 1b). As in Wang et al (2022), APOE E4 carriers (N=71; mean:‐0.43; SD=0.62) exhibited lower CRP circulating levels than non‐E4 bearers (N=265; mean: ‐0.20; SD=0.51; t=3.23, p<0.001), however there were no differences in SyS according to APOE genotypes (t=0.95, p=0.34).

Conclusion

hs‐CRP blood concentrations were predicted by global segregation of functional networks in absence of HPC volume or cognitive status effects. As such, blood derived hsCRP levels may represent an early indicator of middle‐age individual variations in a measure recently reported to predict future cognitive decline (Chan et al. Nat Aging 2021;1:1053) and represent a cognitive resilience mechanism in the face of AD pathology (Ewers et al. Brain. 2021;144:2176).
The Effects of Multiple Doses of Lomecel‐B, Longeveron’ s Cell‐based Therapy, on Alzheimer’s disease: Study Design and Rationale of this Phase 2a Multi‐ center Clinical trial.
Authors: Ramdas Kevin N. , Brody Mark , Herskowitz Brad , Agronin Marc , Ruiz Jorge G , Fuquay Ana , Rodriguez Savannah , Mehranfard Danial , McClain‐Moss Lisa , Gincel Dan , Hare Joshua M. , Oliva Anthony A.
Published: December 2022

Background

Lomecel‐B is an allogeneic medicinal signaling cell (MSC) formulation under clinical investigation for Alzheimer’s disease (AD). We have successfully completed a double‐blinded, placebo‐controlled Phase 1 safety trial, in which Lomecel‐B was found to be safe and tolerable in patients with mild AD, and yielded preliminary evidence supporting potential efficacy. Mechanistically, this included evidence of pro‐vascular and anti‐inflammatory activities. Extending upon these promising results, we present the rationale and design of the next‐phase 2a trial in this program.

Method

The primary objective of this double‐blinded, randomized, and placebo‐controlled Phase 2a trial is to evaluate the safety of multiple doses of Lomecel‐B versus a single dose or placebo. Forty‐eight participants will be equally randomized to four study arms, and will receive intravenous infusions at Weeks 0, 4, 8, and 12, and followed up through Week 39 post‐first infusion. Arm 1 will receive four intravenous infusions of placebo. Arm 2 will receive one infusion of low‐dose Lomecel‐B (2.5×107 cells) followed by three infusions of Placebo. Arm 3 will receive four infusions of low‐dose Lomecel‐B. Arm 4 will receive four infusions of high‐dose Lomecel‐B (108 cells). Enrolled subjects will undergo a multi‐tiered screening process (clinical evaluation, blood‐work, MRI, and PET). Major enrollment criteria are mild AD with confirmatory beta‐amyloid tracer PET, 60‐85 years of age, and a MMSE score of 18‐24.

Safety will be monitored by examining vital signs, physical and neurological exams, laboratory tests (hematology, coagulation, blood chemistry, and urinalysis), and neuroimaging. The secondary objectives are to assess the effects of Lomecel‐B on the cognitive function, and pro‐vascular and anti‐inflammatory biomarkers. Exploratory objectives include neurocognitive, neuropsychiatric, quality‐of‐life, activities‐of‐daily‐living, frailty status, and biomarkers assessments.

Result

This multicenter phase 2a trial has been allowed to proceed by FDA, is IRB approved, and actively enrolling.

Conclusion

This trial is designed to obtain safety and preliminary efficacy data on the effects of a multiple doses of Lomecel‐B on mild AD, with an emphasis on biomarkers related to proposed mechanisms of action (MOAs). We anticipate this trial will have complete enrollment by early 2023, and preliminary safety findings available soon thereafter.
Heart failure associations with cerebral structure: combined analysis from the Multi‐Ethnic Study of Atherosclerosis (MESA) and the SECRET‐II trial of heart failure with preserved ejection fraction
Authors: Schaich Christopher L. , Mujtaba Mohammadtokir , Hugenschmidt Christina E , Jung Youngkyoo , Bertoni Alain G. , Shah Sanjiv J. , Chen Haiying , Kitzman Dalane W. , Hughes Tim M.
Published: December 2022

Background

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in adults 65 and older, but little is known about its relationship with neurocognitive outcomes. We compared brain magnetic resonance imaging (MRI) markers in older adults across stages of preclinical HF and clinical HFpEF.

Method

All participants completed baseline HF evaluation of risk factors, echocardiography, electrocardiography, and cardiopulmonary exercise by ACC/AHA stages; 3T brain MRI; and cognitive testing using harmonized protocols and teams at Wake Forest School of Medicine (2016‐2021). MESA participants without symptomatic HF were assigned to: Stage 0, no risk factors for HF (n = 30); Stage A, risk factors for HF without cardiac structural abnormalities (n = 111); or Stage B, abnormal cardiac structure or function without HF symptoms (n = 66). Participants with stable clinical HFpEF were recruited from the SECRET‐II trial and assigned to Stage C (n = 43). We compared intracranial volume‐adjusted total gray matter (GM), hippocampal, and white matter hyperintensity lesion (WMH) volumes across HF stages using multivariable linear regression adjusted for age, sex, and race, and report standardized least‐squares (LS) means estimates in SD units with 95% CI and Dunnett‐adjusted p‐values (referent = Stage 0).

Result

The combined sample (N = 250) was aged 72±7 years, 64% female, 47% white, and completed 15±3 years of education. Participants with Stage C HFpEF were younger (69±5 vs. 73±7 years, p<0.001) and more likely to be female (85% vs. 59%, p<0.001) than participants in lower stages. Stage B and Stage C participants had significantly lower GM volume than Stage 0 (0.38 [0.07, 0.69] vs. ‐0.12 [‐0.33, 0.09] in Stage B, p = 0.019; ‐0.36 [‐0.64, ‐0.09] in Stage C HFpEF, p = 0.001; Figure A), and Stages A‐C had non‐significant trends toward lower hippocampal volume (Stage 0 vs. Stage C p = 0.053; Figure B) and greater WMH volume (Stage 0 vs. Stages A‐C combined p = 0.073; Figure C). There were no interactions by sex or race.

Conclusion

In this combined analysis from harmonized and diverse cohorts, higher HF stages and clinical HFpEF were associated with significantly lower gray matter volume. Observed trends toward lower hippocampal volume and higher WMH volume in HF Stages A‐C warrant further investigation.
Frequency of TAR DNA‐binding protein 43 (TDP‐43) increases linearly with age in the demented and non‐demented elderly population
Authors: Carlos Arenn F. , Tosakulwong Nirubol , Weigand Stephen D , Boeve Bradley F. , Knopman David S. , Petersen Ronald C. , Murray Melissa E. , Dickson Dennis W. , Josephs Keith A
Published: December 2022

Background

TDP‐43 is a nuclear RNA‐binding protein involved in various neurodegenerative diseases, including Alzheimer’s Disease (AD), and normal aging. It strongly affects cognition and memory loss in AD. Concomitant TDP‐43 pathology increases the likelihood of being cognitively impaired at death.

Method

Mayo Clinic has amassed a large database with 1072 study participants with known TDP‐43 pathology status, who were prospectively recruited and followed in the Mayo Clinic Alzheimer’s Disease Research Center, Mayo Clinic Study of Aging, and Neurodegenerative Research Group. All underwent neurologic, genetic, and neuropathologic evaluations. Amygdala sections immunostained with antibodies against TDP‐43 were screened for TDP‐43‐immunoreactive inclusions and successively staged using the Josephs staging scheme. The frequency of TDP‐43 pathology by age at death was estimated using logistic regression with age modelled using a restricted cubic spline. Models were fit for all cases including the subset of 581 cases with dementia.

Result

Our cohort was predominantly White (99%) with median age at death of 87 years (IQR: 80‐92) and relatively even sex distribution (52% female). About 55% had Braak stage V‐VI and 61% had Thal amyloid phase ≥3. Fifty‐two percent met criteria for intermediate‐high probability AD. TDP‐43‐immunoreactivity (TDP‐43+) was detected in 44% with median TDP‐43 stage of 3 (IQR: 1‐5), and in 54% with a median stage of 3 (IQR: 2‐5) in those with dementia. TDP‐43+ frequency increased approximately linearly with age at death. At 70 years at death, an estimated 30% (95% CI: 25–35) of the cohort was TDP‐43+ versus 33% (CI: 27–40) of those with dementia. By 90 years at death, 49% (CI: 45–52) of the overall cohort and 68% (CI:62‐73) of those with dementia were TDP‐43+.

Conclusion

The results from our large cohort confirm that TDP‐43 pathology frequency increases in elderly White study participants with age of death, independent of cognitive status. Furthermore, TDP‐43 pathology frequency increases to a greater degree with age in those with dementia. Given the clear links between TDP‐43 and impaired cognition, the contribution of TDP‐43 to an individual’s cognitive impairment is likely to increase with age; a dynamic with significant public health consequences given our aging population.
Leveraging American football helmet accelerometer data to estimate associations between cumulative repetitive head impact exposure and chronic traumatic encephalopathy
Authors: Nair Evan S , Daneshvar Daniel H , Rasch Abigail , Abdolmohammadi Bobak , Saltiel Nicole , Uretsky Madeline , Shah Arsal , Baucom Zachary H. , Martin Brett M , Palmisano Joseph , Cherry Jonathan D , Alvarez Victor E. , Huber Bertrand R. , Alosco Michael L , Tripodis Yorghos , Crary John F. , Stein Thor D. , McKee Ann C. , Mez Jesse B.
Published: December 2022

Background

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. We previously showed that duration of American football play is associated with risk and severity of CTE pathology. Helmet accelerometers have been used previously to examine frequency, linear acceleration, and rotational acceleration of hits sustained across youth, high school, and college football. Here we projected this data onto former American football playing brain donors to examine the relationship between cumulative frequency of hits, linear acceleration, and rotational acceleration during players’ athletic careers and CTE pathology.

Method

656 former American football playing brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank were examined for CTE pathology and severity. Years and position of play at each level (youth, high school, college, professional) were acquired through retrospective clinical interviews with brain donors next‐of‐kin. From a literature search of studies using helmet accelerometers, we calculated the mean frequency of hits, linear acceleration (g‐force), and rotational acceleration (rad/sec2) for one year of play at each level‐position combination. These values were projected onto brain donors’ career exposure to derive cumulative frequency of head impacts (CHII), cumulative linear acceleration (CHII‐G), and cumulative rotational acceleration (CHII‐R). Separate logistic regression models examined the relationship of years of play, CHII, CHII‐G, and CHII‐R on CTE status and severity (low vs. high), adjusting for age at death.

Result

The mean (SD) age at death was 59.7 (20.1) and 451 (68.8%) had CTE pathology. Each cumulative measure was significantly associated with presence of CTE (p’s<.001) and severity of CTE (p’s<.001). Based on ROC analyses, CHII‐R (AUC=0.765, p<.001) and CHII‐G (AUC= 0.758, p<.001) performed significantly better than years of play (AUC=0.716) in classifying CTE pathology, and there was no difference between years of play and CHII (AUC=0.698, p=0.25). Similar relationships were observed for CTE severity. Model fit and cross‐validation statistics were also consistent (Table 2).

Conclusion

Among former American football playing brain donors, cumulative linear and rotational acceleration were better predictors of CTE pathology than duration of play or cumulative hits. The findings suggest head impact intensity is an important factor in developing CTE pathology.
Courage in Care Planning: Advance Care Planning Readiness in the Context of COVID19 for Caregivers of Individuals Living with Dementia
Authors: Brandt Katherine , Quimby Megan , Wong Bonnie , Quintiliani Lisa M. , Marchesano Amy , Howe Inola , Paasche‐Orlow Michael K. , Krahn Erin , Krivensky Samantha , O’Chander Raseeka , Volandes Angelo , Dickerson Brad C.
Published: December 2022

Background

Caregivers of individuals living with dementia frequently make medical decisions and develop care plans for future needs of care recipients, often without a clear understanding of those needs. For many, the COVID19 pandemic has exacerbated these challenges. Educational tools are needed to guide caregivers about when and how to raise the topic of advance care planning (ACP).

Method

As part of a larger study about the utility of video decision aids for ACP in dementia, caregivers of individuals living with dementia completed online surveys and watched educational videos about COVID19 and ACP. One day, one week and one month following watching the videos, we assessed ACP‐related knowledge, thoughts, readiness, plans, conversations, and actions in quantitative (validated ACP Engagement Survey) and through qualitative open‐ended questions. Forty‐six caregivers participated. For this analysis, we examined the subset of participants who were not at the most engaged level on the ACP engagement survey. We coded and conducted a content analysis of the open‐ended qualitative questions at one month follow up.

Result

From pre‐post intervention, about 1/3 of participants increased their scores about ACP knowledge, thoughts, plans, and readiness to be a substitute decision‐maker or to make decisions for their loved one if they became very sick (possibly due to Covid). In particular, on one question (how ready are you to discuss with your loved one’s doctor whether or not there are certain health situations that would make your loved one’s life not worth living?), 74% of participants increased their engagement score pre‐ to post‐intervention. In qualitative analyses, 57% reported they engaged in ACP conversations after the intervention.

Conclusion

Immediately after the ACP video intervention, a substantial proportion of caregivers of individuals with dementia increased ratings of knowledge, confidence, and readiness to participate in ACP plans, conversations, and actions for their loved one. One month after the intervention, more than half engaged in ACP conversations. In future research, we will examine participant’s characteristics (e.g., dementia stage of loved one) in relationship to ACP Engagement responses. We plan to evaluate whether exposure to ACP video educational tools increases caregiver confidence in planning for healthcare decisions.
Experiences of Discrimination on Cognitive Function and Aging among the Oldest Old: LifeAfter90 (LA90) Study
Authors: George Kristen M. , Peterson Rachel L. , Gilsanz Paola , Corrada Maria M. , Lor Yi , Meunier Claire C. , Whitmer Rachel A.
Published: December 2022

Background

Discrimination is a primary cause of health inequities, and racial/ethnic disparities in dementia are well documented. However, it is unclear whether longevity into old age indicates overcoming discriminatory experiences. Using data from the LifeAfter90 (LA90) Study, we examined the impact of major lifetime discrimination on cognitive function and decline in those 90+.

Method

LA90 enrolled Asian, Black, Latino, white, and multi‐racial Kaiser Permanente Northern California members who were followed for incident dementia and aged 90+. Discrimination was measured using the Major Experiences of Discrimination Scale. Latent class analysis identified three groups based on responses to the 10‐item scale, gender, and race/ethnicity. Executive function, verbal episodic memory, and semantic memory were assessed every six months with the Spanish and English Neuropsychological Assessment Scales and scores were z‐standardized to baseline. Linear mixed models with random intercepts and slopes associated latent classes of discrimination with cognitive change over 3 waves (mean = 1.2 years). Models adjusted for age, education, cognitive status (normal/mild cognitive impairment‐ accounting for recall bias), practice effects, follow‐up time, and class*time interactions.

Result

Our analytic sample of 445 participants had a mean age of 92.7(SD = 2.3) (Table 1). Class‐1 included mostly white men who reported workplace discrimination and had an average of 2 major discrimination experiences. Class‐2 included white women and non‐white participants who reported little/no discrimination averaging 0 experiences. Class‐3 included all non‐white participants who reported a mean of 4 discrimination experiences. At baseline, using Class‐2 as reference, participants in Class‐1 had significantly better executive function (β(95% CI): 0.28(0.03, 0.52) while Class‐3 did not differ (Table 2). Baseline semantic memory was significantly better for Class‐1 (β(95% CI): 0.33(0.07, 0.58)) and significantly worse for Class‐3 (β(95% CI): ‐0.24(‐0.48, ‐0.00)) compared to Class‐2. We found no class differences in baseline verbal episodic memory. Cognition declined over time across all three cognitive domains (β range: ‐0.31 to ‐0.46), but rate of change did not differ significantly by latent class (Table 3).

Conclusion

Among the oldest old, inequalities in cognition persist after accounting for experiences of lifetime discrimination. Despite participants’ incredible longevity, experiences of discrimination have an indelible association with cognitive health.
Introduction to Veri‐T: A Phase 1 Randomized, Double‐Blind, Placebo‐Controlled, Multicenter Trial of Verdiperstat in Patients with svPPA Due to FTLD‐TDP
Authors: Ljubenkov Peter A. , Staffaroni Adam M. , Rojas Julio C. , VandeVrede Lawren , Koestler Mary , Sulse Tayler A , Moreton Julia , Horiki Sheena , Heuer Hilary W. , Grant Ian , Irwin David J. , Boeve Bradley F. , Rosen Howard J. , Knopman David S. , Bowser Robert , Grossman Murray , Qureshi Irfan , Boxer Adam L.
Published: December 2022

Background

TAR DNA‐binding protein 43 (TDP‐43) mislocalization is present in over 50% of patients with frontotemporal dementia and about 20% of patients with Alzheimer’s disease, but there is still an unmet need for clinical trials targeting sporadic TDP‐43 pathology in patients with dementia. The semantic variant of primary progressive aphasia (svPPA) is highly predictive of frontotemporal lobar degeneration with TDP‐43 mislocalization (FTLD‐TDP) and presents an ideal cohort in which to explore therapeutics with potential benefit across the spectrum of TDP‐43 pathology. Oxidative stress promotes mislocalization of TDP‐43 in neurons and may be a viable therapeutic target in svPPA and other FTLD‐TDP disorders. Verdiperstat is a potent, oral, CNS penetrant, myeloperoxidase inhibitor that reduces production of oxidative species from microglia. The Veri‐T trial (NCT05184569) explores the therapeutic potential of verdiperstat and is the first clinical trial to focus on patients suffering from svPPA.

Methods

Veri‐T is a multisite, phase 1, randomized, double‐blind, placebo‐controlled trial. N = 64 participants with svPPA will be randomized 3:1 to oral verdiperstat (titrated to a dose of 600mg BID) or placebo for 6 months of double‐blind therapy. Neuropsychological assessments, plasma, CSF, and volumetric brain imaging are collected prior to and upon conclusion of treatment. Recruitment is ongoing at 5 ARTFL LEFFTDS Longitudinal FTLD (ALLFTD) research network clinical centers.

Results

The primary objective is to determine the safety and tolerability of verdiperstat in svPPA. The secondary objective is to determine the pharmacokinetic profile of verdiperstat in this cohort. Exploratory endpoints are focused on identifying potential pharmacodynamic effects and identifying endpoints for future efficacy trials including plasma myeloperoxidase activity, CSF biomarkers of glial activity (chitinase‐family proteins), neurodegeneration (neurofilament light chain), and unbiased CSF proteomics (Somalogics), as well volumetric MRI changes unique to svPPA, and cognitive and language impairments measured using the ALLFTD Mobile App.

Conclusion

The Veri‐T trial examines the safety, tolerability and pharmacokinetic properties of verdiperstat in svPPA, and explores novel pharmacodynamic biomarkers and outcome measures that could be employed in future efficacy studies. Veri‐T is the first multicenter clinical trial of a potentially disease modifying agent for svPPA, and the first to leverage resources of the ALLFTD network.
Plasma Biomarkers of Amyloid and Neurodegeneration predictive of Neuropathologic Scales of Cerebrovascular Disease
Authors: Graff‐Radford Jonathan , Mielke Michelle M. , Hofrenning Ekaterina I , Kouri Naomi , Lesnick Timothy , Moloney Christina M. , Rabinstein Alejandro , Cabrera‐Rodriguez Janisse N , Rothberg Darren M , Przybelski Scott A. , Petersen Ronald C. , Knopman David S. , Dickson Dennis W. , Nguyen Aivi T. , Murray Melissa E. , Vemuri Prashanthi
Published: December 2022

Background

Blood‐based biomarkers of amyloid and neurodegeneration are increasingly used in clinical trials and entering clinical use. Differentially mapping the plasma markers to post‐mortem neuropathology in a community‐based sample is critical for interpretation.

Method

We identified 64 Mayo Clinic Study of Aging (MCSA) participants with antemortem plasma markers (Aβ42, Aβ40, NfL, T‐tau, Aβ42/40 ratio) measured on the Quanterix Simoa HD‐1 analyzer and with postmortem neuropathologic assessments of Alzheimer’s pathology (Braak tangle stage, Thal phase, neuritic plaque burden) and cerebrovascular pathology (Strozyk scale focused on macrovascular brain changes and Kalaria scale focused on detailed micro‐ and macro‐ vascular brain changes). Weighted linear regression models with adjustment for time between plasma markers and death were conducted with exact permutation tests to evaluate the relationships between antemortem plasma and postmortem neuropathology markers.

Result

Higher plasma NfL levels and Aβ42/40 ratio were associated with both cerebrovascular neuropathologic scales (p<0.05) but were not associated with Braak neurofibrillary tangle stage, neuritic plaque score, or Thal stage (p>0.5). Plasma T‐tau was not associated with any pathological assessment. Plasma Aβ42/40 and NfL explained up to 18% of the variability in cerebrovascular neuropathologic scales.

Conclusion

In this community sample of participants predominantly without dementia, plasma markers for amyloid (Aβ42/40) and neurodegeneration (NfL) were associated with cerebrovascular neuropathology at autopsy. NfL is a non‐specific marker of brain injury, therefore, its association with cerebrovascular neuropathology was in the expected direction. The association between greater cerebrovascular neuropathology and elevated Aβ42/40 requires further investigation. These findings provide evidence that cerebrovascular disease may significantly influence levels of plasma biomarkers proposed for Alzheimer’s disease. This information will be important to consider for accurate clinical interpretation of the proposed biomarkers.
Multi‐center study reveals impairment of cortical tissue oxygenation during rising blood CO2 tension in MCI and AD patients
Authors: Marmarelis Vasilis , Billinger Sandra A , Chui Helena C , Joe Elizabeth B , Shin Dae , Cardim Danilo , Hashem Suhaib , Aaron Stacey E , Cullum Munro , Kelley Brendan J. , Zhang Rong
Published: December 2022

Background

An ongoing multi‐center study of a consortium of Alzheimer’s Disease Centers in Los Angeles (USC), Dallas (UT‐SWMC) and Kansas City (KUMC) has explored quantitatively the dynamics of the homeostatic mechanism that maintains adequate cortical tissue oxygenation during a rise in blood CO2 tension. The results from cognitively normal subjects and MCI/AD patients were compared to assess differences in the dynamics of this important homeostatic mechanism.

Method

Quantification of the dynamics of cortical tissue oxygenation was achieved through extraction of predictive models from five‐minute data‐records of spontaneous fluctuations in cortical tissue oxygenation (CTO), measured non‐invasively via near infrared spectroscopy at the prefrontal cortex, and the associated fluctuations in arterial blood pressure (ABP) and end‐tidal CO2 (etCO2). Using a novel kernel‐based modeling methodology, we analyzed the time‐series data from 25 MCI patients, 7 AD patients and 45 age‐matched cognitively normal controls (NC) and obtained predictive models of the dynamic effects of ABP and etCO2 (viewed as a proxy for blood CO2 tension) upon CTO. These predictive models were used to quantify the dynamics of cortical CO2 reactivity (CCR) in each participant, as the time‐average of the model‐predicted CTO response to unit‐step etCO2 change over the first 30 sec. The obtained CCR indices were used to evaluate the differences between NC and MCI/AD patients.

Result

The obtained CCR indices were significantly different for the 32 patients (MCI and AD lumped together due to small number of AD) vs. 45 age‐matched controls (p= 0.0083), with respective mean (SD): 0.014 (0.108) vs ‐0.059 (0.119). This is illustrated in Figure 1, where the average model‐predicted CTO responses to a unit‐step change of etCO2 are shown for 32 MCI/AD patients (red line) and 45 controls (blue line). Note the negative values of the average CTO response for patients (red line) to unit‐step increase of etCO2 that indicates polarity reversal of the normal CO2 vasomotor reactivity (blue line).

Conclusion

Quantitative analysis of cortical oxygenation dynamics under resting spontaneous conditions in 32 MCI/AD patients relative to 45 age‐matched controls revealed a significant impairment of the homeostatic mechanism that maintains adequate oxygenation of cortical tissue during a rise in blood CO2 tension.
The Lived Experience of Individuals with Dementia and Care Partners in Latin America and How Researchers Can Build Stronger Partnerships to Improve Research
Authors: Llibre‐Guerra Jorge J , Babulal Ganesh M
Published: December 2022

Background

Researchers working on studies of dementia in Latin American and Caribbean (LAC) countries encounter numerous challenges, in particular, access to financial resources due to limited funding and operational barriers which limit the possibility of recruiting a diverse cohort from the LAC. Addressing challenges to access research is important to ensure outcomes of research are applicable more broadly to individuals living in all countries. Engaging with individuals that have the lived experience of dementia and caregiving is key to addressing barriers to participation.

Methods

The panelist will be selected by the Washington University research team and will live in either Latin America or the Caribbean. The panelist will share their lived experience with ADRD diagnosis, care, and research participation. The panelist will provide examples of the unique challenges faced in accessing care and research. They will share what researchers can do to build better partnerships within individuals living in Latin American or Caribbean countries.

Results

This session will highlight the perspective of individuals living in an economically developing nation, specific to dementia research, and will offer the opportunity for further understanding around the experience of individuals in minoritized communities. This session aims to benefit researchers by providing perspectives crucial to the development of strategies to facilitate engagement with more demographically diverse communities across the globe.

Conclusion

The voice of individuals from Latin America is essential to include when discussing research priorities and addressing the challenges to increase diverse research participation. Greater inclusivity in research will improve relevance of findings, and sharing diverse perspectives is a first step to build meaningful partnerships.
Innovative Methods to Gather, Understand, And Incorporate Diverse Lived Experiences Into Dementia Research
Authors: Walter Sarah , Pierce Aimee , Jackson‐Pope Lenore , Rentz Dorene M. , Coppelman Nancy , Lingler Jennifer H , Babulal Ganesh M , Aggarwal Neelum T. , Largent Emily A. , Glover Crystal M
Published: December 2022

Background

Aging and dementia researchers continue to face challenges in recruiting and retaining participants who represent demographically diverse communities. This continued and critical lack of representation threatens the generalizability and applicability of countless study findings and severely diminishes the field’s impact on clinical outcomes. Recruitment science evidence strongly recommends that to achieve equity researchers should design and conduct research hand‐in‐hand with the input of potential and current participants, as well as their loved ones. To do so, partnerships between researchers and demographically diverse communities must be built and maintained before, during, and after individual studies. Indeed, literature indicates that persons from demographically diverse communities want to contribute to research, even beyond traditional research participation, including serving on community advisory boards and sharing their lived experiences in public forums. This symposium will discuss innovative methods currently being used to gather, understand, and incorporate diverse lived experiences with the goal of improving aging and dementia research generalizability and applicability.

Method

We will discuss research methods that various stakeholders—including researchers, study sponsors, funders, and participant groups—can utilize throughout the research process, from conceptualization and conduct to dissemination.

Result

This presentation will highlight community‐based and participant‐centered recruitment and retention approaches that promote understanding and incorporating diverse older adults’ and carers’ lived experiences. Approaches that will be discussed include, lived experiences panels, community and/or participant advisory boards, research ambassadors, and inclusion in scientific conferences. Furthermore, this session will feature a lived experience panel comprised of demographically diverse persons along the dementia continuum, from at‐risk to living with dementia, and their care partners. This session can benefit researchers, clinical trialists, and the field of aging and dementia research, by expounding on the importance of and developing strategies to meaningfully engage with demographically diverse communities.

Conclusion

Meaningful understanding and incorporation of the lived experiences of persons representing demographically diverse backgrounds offers clear benefits to aging and dementia researchers to improve the applicability and translatability of research findings. The participant’s voice is essential in setting research priorities and addressing research‐related challenges to ultimately increase diverse research participation and facilitate equity in aging.
Clinical and Neuropathological Correlates of Substance Use Disorders in Brain Donors Exposed to Repetitive Head Impacts
Authors: Rasch Abigail , Tripodis Yorghos , Martin Brett M , Palmisano Joseph , Katz Douglas I , Dwyer Brigid , Daneshvar Daniel H , Goldstein Lee E , Kowall Neil W , Stern Robert A , Huber Bertrand R. , Stein Thor D. , McKee Ann C. , Mez Jesse B. , Alosco Michael L
Published: December 2022

Background

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI) like those from American football. Causes of cognitive and neuropsychiatric symptoms (e.g., neurobehavioral dysregulation) in CTE are unclear. Substance use disorders (SUDs) are common among individuals with autopsy‐confirmed CTE, but their association with CTE and related symptoms are unknown. We examined the association between SUDs and CTE pathology, and cognitive and neuropsychiatric symptoms in deceased football players.

Methods

The sample included 429 deceased football players from the UNITE brain bank. CTE was neuropathologically diagnosed. Informant interviews assessed SUD history. The independent variable included substance use treatment history, an indicator of SUD less influenced by recall error. Informants completed standardized scales of cognitive function (Cognitive Difficulties Scale, Functional Activities Questionnaire, BRIEF‐A Metacognition Index [MI]), mood (Geriatric Depression Scale [GDS‐15]), and neurobehavioral dysregulation (BRIEF‐A Behavioral Regulation Index [BRI], Barratt Impulsiveness Scale [BIS‐11]). Linear or logistic regressions test the association between substance use treatment history and CTE status, cumulative p‐tau burden (sum of p‐tau severity ratings across 11 brain regions, n = 370), and each clinical scale, controlling for age and years of football play. Cumulative p‐tau burden was added as a covariate in clinical models.

Results

Tables 1–3 show sample characteristics. 313/429 had autopsy‐confirmed CTE. Alcohol use disorders were more common (n = 177, 41.3%) than illicit (n = 70,16.3%) and prescription (n = 47, 11%) drug use disorders. Approx. 23% (n = 100) had a substance use treatment history, which was not associated with CTE (p = 0.21) or p‐tau burden (p = 0.14). Substance use treatment history was associated with neurobehavioral dysregulation (BRI: beta = 8.17, 95% CI = 3.92‐12.41, p<0.01; BIS‐11: beta = 8.90, 95% CI = 5.11‐12.69, p<0.01) and greater depression symptoms (GDS‐15: beta = 2.17, 95% CI = 1.08‐3.26, p<0.01). Besides the MI (beta = 5.09, 95% CI = 0.67‐9.51, p = 0.02), there was no association with cognitive scales (ps>0.05). Cumulative p‐tau burden was associated with neurobehavioral dysregulation (BRI, p<0.01) and all cognitive scales (ps<0.05).

Conclusions

In former football players, SUDs are unlikely to affect risk for CTE, but can contribute to clinical symptoms especially neurobehavioral dysregulation. These findings stress the role of tau and non‐tau causes of neurobehavioral dysregulation among football players. However, p‐tau is likely a key driver of cognitive symptoms.
Military Service and Cognitive Decline after age 90: The LifeAfter90 Study
Authors: Lor Yi , George Kristen M. , Peterson Rachel L. , Gilsanz Paola , Corrada Maria M. , Meunier Claire C. , Soh Yenee , Kawas Claudia H. , DeCarli Charles S. , Whitmer Rachel A.
Published: December 2022

Background

Studies have shown that military veterans are at higher risk of dementia. Less is known about cognitive aging and decline, especially among veterans who have survived past age 90. We investigated the association of military service with cognitive function and decline in the LifeAfter90 (LA90) cohort.

Method

LA90 included Asian, Black, Latino, White, and multi‐racial individuals aged 90 years or more without a history of dementia diagnosis at recruitment. We assessed active US military service via self‐report at baseline. Due to the small number of women reporting military service (n = 5), analyses were restricted to men participants. Cognitive domains of executive function, verbal episodic memory, and semantic memory were assessed every six months using the Spanish and English Neuropsychological Assessment Scales (z‐standardized). Linear mixed models with random intercepts and slopes evaluated the association between military service with cognitive change over 3 visits (mean = 1.2 years), adjusting for years since baseline, baseline age, education, practice effects (indicator variables for visits 1 and 2), and interview mode (phone vs in‐person).

Result

Of the 195 participants, 151 (77%) had served in the active military (Table 1). Those who served in the military had, on average, higher baseline executive function (β[95% CI] = 0.33[0.13, 0.54]) and semantic memory (β[95% CI] = 0.53[0.24, 0.82]) compared to those who did serve in the military; there was no difference in baseline verbal episodic memory (Table 2; Model 2). Those who served in the military had slower decline in verbal episodic memory (β[95% CI] = 0.35[0.07, 0.63]), compared to those who did not serve. Point estimates suggest slower decline in executive function and semantic memory for those who served in the military but were not significant.

Conclusion

Among the oldest‐old men, military service was associated with higher baseline executive function and semantic memory, and slower decline in verbal episodic memory compared to not having served in the military. Future research may explore whether veteran benefits in educational or financial support, such as the GI Bill, help explain the apparent protective effects of veteran status.