bluuebunny/crossref_metadata_2025 huggingface dataset:
Alzheimer’s disease specific MRI brain regions are differentially associated with accelerated decline as defined using sigmoidal cognitive turning point methodology in amyloid‐positive AIBL participants
Authors: Gillis Cai , Cespedes Marcela Ines , Maserejian Nancy Nairi , Dore Vincent , Maruff Paul , Fowler Christopher , Rainey‐Smith Stephanie , Villemagne Victor L , Rowe Christopher , Martins Ralph N , Vacher Michael , Masters Colin L , Doecke James D
Published: December 2022

Background

Variability in cognitive decline among adults with Alzheimer’s disease (AD) is seen across studies. While such variability is often modelled using linear models, in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, application of a sigmoidal methodology has shown excellent precision in modelling cognitive and biomarker changes. Here we expand these findings by examining associations of brain volumes in AD specific Regions of Interest (ROIs) with accelerated cognitive decline among amyloid‐beta positive (Ab+) AIBL participants.

Method

Longitudinal cognitive scores for the AIBL PACC, Language, Visuospatial functioning and CDR‐SB were mapped to sigmoidal trajectories, with a threshold defining the inflection point of accelerated cognitive decline. Participants to the left of the threshold were classified as having non‐accelerated decline (non‐accelerators), and participants beyond the threshold were classed as accelerators (Figure 1B). Using these classifications, we investigated differences in 16 ICV corrected ROI (left and right hemispheres pooled) for reductions in brain volume via generalised linear models adjusted for age, gender, and APOE‐e4 status. Three participant subgroups were tested: 1) Ab+/Tau unknown, 2) Ab+/Tau‐ and 3) Ab+/Tau+. Significant t‐values for the summed ROI volumes were mapped on a standard brain mesh for visualisation.

Result

Of regions tested, two stood out consistently amongst top markers in each of the participant subgroups and cognitive outcomes: 1) supramarginal volume and 2) middle temporal volume (Figure 1C). Largest volume differences between accelerators and non‐accelerators were seen in the Ab+/Tau+ group; whilst smallest p‐values were in the Ab+/Tau unknown group due to a larger sample size (Table 1). Brain mesh visualization showed most of the AD signature ROIs altered in accelerator groups as compared with non‐accelerator groups. Figure 1D shows the AD signature for each cognitive outcome amongst the Ab+/Tau participant group. Top ranked ROI for the left being middle temporal volume (T=7.10, PACC) and supramarginal volume (T=7.10, CDR‐SB).

Conclusion

Sigmoid analyses of MRI using binary cognitive scores show decreased ROI volumes in AIBL Ab+ participants with accelerated cognitive decline. This effect was mediated by known information on Tauopathy. Whilst effect sizes were high, smaller sample sizes in some groups affected p‐values and should therefore be replicated in larger samples.
Discrete white matter hyperintensity (WMH) growth quantification is superior to measurements of total longitudinal WMH volume change: implications for clinical trials in VCID
Authors: Bahrani Ahmed Ali , Barber Justin M , Gold Brian T. , Ali Doaa , Powell David K , Van Eldik Linda J , Goldstein Larry B , Wilcock Donna M , Jicha Gregory A
Published: December 2022

Background

Small vessel ischemic disease (SVID) is a major risk factor for late‐life cognitive impairment and dementia (VCID). White matter hyperintensities (WMH) are a SVID biomarker that can be detected on MRI FLAIR imaging. Prior studies show dynamic change in WMH volumes that increase and decrease within subjects over time. We reported a method to quantify discrete WMH volume growth and regression in individuals over one‐year with instrumental validation performed within the MarkVCID consortium. The present study provides preliminary evidence for the clinical relevance of this methodology.

Method

3D MRI T1‐weighted and FLAIR images at baseline and 12‐month follow‐up visits for sixty‐one participants (mean age 74 ± 5.9 years, 31 women) were analyzed. The Stroop test was administered using the CANS‐MCI computerized battery. WMH growth and regression were quantified for all participants. A linear regression model was used to assess the association of dynamic WMH changes with Stroop performance.

Result

WMH growth, but not regression or total WMH volume changes was associated with Stroop performance at the 12‐months (β = ‐0.24, P = 0.02) after controlling for sex, and age (graph).

Conclusion

These data show that WMH growth, but not regression or total WMH volume change, was associated with a decline in performance on the Stroop test over12‐months. These findings highlight the importance of studying dynamic, within subject, WMH growth and regression rather than solely focusing on longitudinal change in total WMH volume measurements. Measurement of WMH growth may help reduce sample sizes, facilitate clinical trial conduct, and optimize the potential to identify interventions intended to mitigate SVID contributions to VCID.
The potential protective benefit of personality on subjective cognitive decline related worry: Results from the Canadian Longitudinal Study on Aging (CLSA)
Authors: Hopper Shawna , Hammond Nicole G , Taler Vanessa , Stinchcombe Arne
Published: December 2022

Background

Subjective cognitive decline (SCD), a self‐reported decline in cognition, may be a risk factor for Alzheimer’s disease. Recently, SCD‐related worry has been implicated in predicting the progression from SCD to further cognitive decline. Certain personality traits have been linked to cognitive health (i.e., conscientiousness, emotional‐stability, and openness to experience), but little is known about the association between personality traits and worry related to perceived cognitive decline.

Method

Analyzing data from the Canadian Longitudinal Study on Aging (CLSA), a large national study of participants aged 45‐85 at baseline, we sought to identify prospective psychosocial correlates of SCD‐related worry. At baseline, known correlates of cognition (e.g., depression) were measured, as well as the primary predictor of interest, personality traits, which were measured using the Ten‐Item Personality Inventory (TIPI). SCD and SCD‐related worry were measured three years later. Participants who positively endorsed SCD at follow‐up were asked a single‐item assessing their worry about their self‐reported memory decline. Response options ranged from disagree to agree. Multiple imputation using chained equations (MICE) was conducted to account for missing data. An ordinal logistic regression model was used to estimate the odds of reporting greater SCD‐related worry (n = 27,745).

Result

Many psychosocial measures were associated with greater SCD‐related worry, for example, being a woman (OR = 1.35, CI: 1.25‐1.45), being younger (OR = 0.99, CI: 0.97‐0.99), and elevated depression symptoms (OR = 1.44, CI: 1.32‐1.58). With respect to personality traits, higher levels of certain traits were associated with reduced odds of SCD‐related worry: extraversion (OR = 0.96, CI: 0.95‐0.98), conscientiousness (OR = 0.95, CI: 0.92‐0.97), and emotional stability (OR = 0.86, CI: 0.84‐0.88). Openness to experience (OR = 1.01, CI: 0.99‐1.03), and agreeableness (OR = 1.00, CI: 0.97‐1.03), were not associated with SCD‐related worry.

Conclusion

Higher levels of extraversion, conscientiousness, and emotional stability were associated with higher worry regarding perceived decline in cognitive functioning. This information may help identify individuals at a greater risk of future cognitive impairment and dementia.
Short antibiotic treatment followed by regular administration of acid suppressant (proton pump inhibitor) reduce AB42 load in the brain and in the gut.
Authors: Chevalier Claire , Marizzoni Moira , Tournier Benjamin , Paquis Arthur , Gueorguiev Boris R , Millet Philippe , Frisoni Giovanni B
Published: December 2022

Background

Fecal microbiota transplantation (FMT) from healthy mice, microbiota depletion with antibiotic treatment (ABT) or with germ free mice have been associated with a reduction of cerebral amyloid load in Alzheimer’s disease (AD) mice models, indicating that the gut microbiota can modulate amyloid load in the brain. Interestingly, amyloid can also deposit in the gut, particularly within proximity to vasculature, nerves, and nerve plexuses. Additionally, acid suppressant drug such as proton pump inhibitors (PPI) have been shown to modify the gut microbial population. Here we postulate that ABT+PPI could modulate the gut microbiota and amyloid load in the gut and in the brain.

Method

Sixty female, two‐year old 3xTg mice (APPSWE, PS1M146V and TauP301L) were divided in 2 groups and received: (1) 2‐weeks of ABT to deplete the microbiota followed by recurrent PPI administration simultaneously with (FMT) once a week for 2 months or (2) FMT only at same frequency. The FMTs consisted in i) water, ii) litter mate mice and, iii) bacteria isolated from 1 young and 1 cognitively unimpaired elderly donor to test different microbiota.

Result

After 60 days of treatment, Ab42 and Ab40 were measured by ELISA in the hippocampus and the colon. We observed that ABT‐PPI treatment reduced the soluble and insoluble form of Ab42 in the hippocampus (ANOVA p<0.05) and, interestingly, also in the colon (ANOVA p<0.05), independently of the microbiota transplanted. This was specific to the Ab42 isoform as no differences was observed in the levels of AB40.

Conclusion

The results suggest that ABT‐PPI can reduced Ab42 in the brain as well as in the gut in an AD mice model, independently of the microbiota transplanted. The link between the amyloid in the gut and in the brain remain a black box. More research is needed to rule out that the Ab detection in the gut is not due to randomly deposited circulating amyloid from blood. Also, the short ABT intervention and the 2 months delay before sample collection suggests that the driver of the effect observed is the PPI. This will be confirmed by testing the administration of PPI only.
Assessment of decisional capacity for Alzheimer’s disease PET disclosure among cognitively symptomatic individuals
Authors: Rahman‐Filipiak Annalise , Feldman Sara J , Lesniak Mary , Milliken Marie , Roberts J. Scott , Hampstead Benjamin M.
Published: December 2022

Background

Older adults are highly interested in learning their Alzheimer’s disease (AD) positron emission tomography (PET) amyloid‐beta (Aβ) and tau results. However, knowledge about the meaning, uses, and risks of learning personal biomarker results is variable. Tools are needed to assess decisional capacity prior to biomarker disclosure, particularly for individuals with cognitive impairment.

Methods

30 participants (46.7% female; 93.3% white, age = 71.9±7.14 years) diagnosed with either mild cognitive impairment (MCI; 60.0%) or dementia‐Alzheimer’s type (DAT; 40.0%) completed Aβ and tau PET, an interactive education session and results disclosure decision‐making assessment. When available, cognitively unimpaired care partners (n = 27) attended these sessions and their ability to demonstrate decisional capacity for participant biomarker disclosure was assessed. Decisional elements evaluated included understanding of the meaning of biomarker results, appreciation of risks and benefits of engaging in disclosure, communication of a choice to learn the participant’s biomarker results, and demonstration of a rationale for engaging (or not) in disclosure. Chi‐squared tests were used to assess whether successful demonstration of each element differed by diagnosis.

Result

More participants with MCI (77.8%) than participants with DAT (25.0%) demonstrated disclosure decisional capacity (χ2 = 8.17, p = .008). Across the full sample, participants had the most difficulty understanding the difference between AD and DAT (34.6% incorrect), the meaning of elevated amyloid (19.0% incorrect) or tau (10.0% incorrect), and biomarker disclosure risks (19.0% incorrect). Compared to participants with DAT, those with MCI were more likely to demonstrate understanding of biomarker results (33.3% DAT v. 77.8% MCI; χ2 = 5.93, p = .024) and appreciation of personal benefits and risks of biomarker disclosure (33.3% DAT v. 83.3% MCI; χ2 = 7.75, p = .009). There were no differences in demonstration of rationale or communication of choice by diagnosis. All care partners demonstrated adequate decisional capacity for disclosure of the participant’s PET results.

Conclusion

Appreciation and understanding, two elements rarely evaluated in clinical or research settings, are more challenging than rationale or choice for cognitively impaired participants to demonstrate. Prior to disclosure, education should emphasize the possible meaning, usefulness, and risks of PET amyloid and tau information. Family or care partner disclosure decision‐making assessment should be a standard part of disclosure protocols.
Cardiovascular health and resilience to cognitive decline and impairment among diverse Hispanics/Latinos: Results from the Study of Latinos‐ Investigation of Neurocognitive Aging (SOL‐INCA)
Authors: Tarraf Wassim , Stickel Ariana M , Wu Benson , Brewer James B. , Gallo Linda C , Talavera Gregory A , Isasi Carmen R , Kaplan Robert , Lipton Richard B. , Daviglus Martha L , Zeng Donglin , Pike James R. , Schneiderman Neil , Rundek Tatjana , Sofer Tamar , Fornage Myriam , DeCarli Charles S. , Fletcher Evan , Branch Craig , Zhou Xiaohong , Gonzalez Hector Leonardo
Published: December 2022

Background

Cardiovascular disease contributes to cognitive impairment and dementia, particularly among populations facing health disparities. However, the long‐term effects of cardiovascular health on later cognitive health have not been examined among Hispanics/Latinos. Therefore, we examined relationships between cardiovascular health with change in cognition and mild cognitive impairment (MCI) among diverse Hispanics/Latinos.

Method

Hispanics/Latinos (n = 6,223, ages 50‐86 years) were enrolled in the Study of Latinos ‐ Investigation of Neurocognitive Aging (SOL‐INCA), an ancillary study of the Hispanic Community Health Study/SOL (HCHS/SOL). Cardiovascular health was the primary exposure, measured using the American Heart Association’s Life’s Simple 7s (LS7). Outcomes of interest included 7‐year performance in cognition, change in cognition, and MCI prevalence. Cognitive outcomes included measures of learning and memory, verbal fluency, executive functioning and processing speed, and a global composite (average of the z‐scores on each test). Survey linear regressions were used to separately model the associations between LS7 with outcomes of interest, controlling for age, age2, education, language preference, Hispanic/Latino background, and income.

Results

Better cardiovascular health (higher LS7 Score) was associated with higher global cognitive performance (βGlobal = 0.028 [SE = 0.005], p<0.001). These associations were evident in learning (βB‐SEVLT‐Sum = 0.024 [SE = 0.007], p<0.01), memory (β = 0.024B‐SEVLT‐Recall [SE = 0.008], p<0.01), verbal fluency (β = 0.039WF [SE = 0.008], p<0.001), executive functioning and processing speed (βDSS = 0.027 [SE = 0.007], p<0.001 and βTrails A = ‐0.022 [SE = 0.007], p<0.01). We also observed significant associations between better cardiovascular health and improved global cognitive change (β = 0.023 [SE = 0.008], p<0.01), evident also for learning (βB‐SEVLT‐Sum = 0.017 [SE = 0.008], p<0.05), executive functioning and processing speed (βDSS = 0.034 [SE = 0.008], p<0.001). Lastly, better cardiovascular health decreased the odds ratios for prevalent MCI (ORMCI = 0.90 [0.842, 0.959], p<0.01).

Conclusion

Cardiovascular health was protective of 7‐year cognitive aging and associated with reduced MCI prevalence. Our findings suggest that cardiovascular health may improve resilience to cognitive decline and impairment amongst diverse Hispanics/Latinos, which could prove instrumental in public health efforts for reducing dementia disparities facing Hispanics/Latinos.
Quantifying longitudinal cognitive resilience to Alzheimer’s disease and other neuropathologies
Authors: Wagner Maude , Wilson Robert S. , Leurgans Sue E. , Boyle Patricia A , Bennett David A , Grodstein Francine , Capuano Ana W.
Published: December 2022

Background

Cognitive resilience (CR) has been defined as the continuum of better (or worse) than expected cognition, given the degree of neuropathology. To quantify this concept, existing approaches focus on either cognitive level at a single timepoint (Figure 1A) or slopes of cognitive decline (Figure 1B).

Method

In a prospective study of 1,215 participants, we created a continuous measure of CR defined as the mean of differences between estimated person‐specific and marginal cognitive levels over time, after accounting for neuropathologies (Figure 1C).

Result

Neuroticism and depressive symptoms were associated with all CR measures (P‐values<.012); as expected, cognitive activity and education were only associated with the cognitive‐level approaches (P‐values<.0002). However, compared with the existing CR measures focusing on a single measure or slopes of cognition, our new measure yielded stronger relations with risk factors.

Conclusion

Defining CR based on the longitudinal differences between person‐specific and marginal cognitive levels is a novel and complementary way to quantify CR.
Improved biomarker associations using neuropsychological criteria versus ADNI criteria for diagnosis of MCI in Vietnam‐era veterans with head injury histories
Authors: Ly Monica T. , Bondi Mark W. , Edmonds Emily C. , Delano‐Wood Lisa
Published: December 2022

Background

Compared to conventional Petersen/Winblad criteria for mild cognitive impairment (MCI), our prior work has shown that neuropsychological or “actuarial” criteria more accurately predicts progression to dementia, and is more strongly associated with Alzheimer’s disease (AD) biomarkers and imaging profiles. However, research to date has been conducted in relatively healthy samples with few comorbidities. Given that history of traumatic brain injury (TBI) and post‐traumatic stress disorder (PTSD) is common in older veteran populations, and both conditions are well‐documented risk factors for AD, we compared Jak/Bondi neuropsychological and ADNI MCI criteria to examine cross‐sectional cognitive and biomarker profiles in a well‐characterized sample of Vietnam‐era veterans with history of TBI and PTSD.

Method

186 veterans (mean age = 70.11) from the DoD‐ADNI study with history of TBI were evaluated for MCI using (1) ADNI criteria: subjective memory concern, objective memory impairment using WMS‐R Logical Memory, and Clinical Dementia Rating Global = 0.5; and (2) neuropsychological criteria: >1 standard deviation (SD) below age‐appropriate norms on two tests within any cognitive domain, or >1 SD below age‐appropriate norms on one test across all domains. Accounting for age and education, linear regression evaluated relationships between MCI diagnosis and AD biomarkers (Aβ42, total tau [t‐tau], and phosphorylated tau [p‐tau]). Logistic regression evaluated whether PTSD symptoms (CAPS total score) predicted MCI.

Result

Roughly 17% of the sample met neuropsychological criteria for MCI, while 13% met ADNI criteria. Agreement between criteria was poor (κ = .17). APOE4 carrier status did not predict diagnosis by either criteria. MCI diagnosis using neuropsychological criteria was associated with higher t‐tau (p = .049) and p‐tau (p = .04), but not Aβ42 (p = .15), while ADNI diagnosis was not associated with any biomarkers (p>.05). PTSD symptoms predicted MCI diagnosis using ADNI (p = .005) but not neuropsychological criteria (p = .19).

Conclusion

Findings showed that MCI diagnosis using sensitive neuropsychological methods is more strongly associated with AD biomarkers than conventional diagnostic methods. Additionally, ADNI criteria may be capturing false‐positive diagnoses secondary to PTSD. MCI diagnostics benefit from the incorporation of comprehensive neuropsychological methods, particularly in complex populations with medical and psychiatric comorbidities.
The Impact Treatment Imbalance and Patient Enrichment has on Study Sample Size in Early/Mild Alzheimer’s Disease
Authors: Buitendyk Melanie , Rosen Allan , Barnum CJ , Tesi RJ
Published: December 2022

Background

Disease modification trials in Alzheimer’s Disease (AD) are typically conducted in Early AD patients, combination of patients with mild cognitive impairment (MCI) and mild AD (mAD), despite vastly different progression rates between these two AD groups. A large sample size (SS) is required to show efficacy due to low MCI APRs. Furthermore, treatment group imbalances in patients likely to progress (PLP) may lead to underpowered studies. We quantified the impact on SS of: (1) potential treatment group imbalances in PLPs and (2) PLP enrichment strategies.

Method

Roughly 10% of patients diagnosed with MCI progress to dementia within 1 year (Mitchell, 2009). Patients with mAD progress at an APR of 25% (Davis, 2018). To assess the impact on SS, we considered a 1:1 randomized study, stratified by equally sized AD strata (MCI, mAD) with 90% power and 1‐sided 0.025 level Cochran Mantel Haenszel (CMH) test to detect lower APRs in the experimental arm compared to placebo for an odds ratio (OR) = 0.5. To assess the impact of treatment group imbalances in PLPs, we computed SS for various departures from a balanced study. SS calculations were performed after enriching the APR in the MCI or both AD strata.

Result

SS increases as more PLPs are assigned to the experimental arm than the control arm. For example, SS is 852 when PLPs are balanced 50%:50% between arms and 932 with a 55%:45% imbalance. When the MCI population is enriched to a 20% APR, SS is 672 for a balanced study and 732 with a 55%:45% imbalance. The following figure displays the impact of a PLP enrichment strategy on SS by increasing APRs by 5% in each AD strata, assuming no treatment group imbalances in PLPs.

Conclusion

Prediction (Davis, 2018) and machine learning (James, 2021) models have been developed to classify PLPs. Using such tools to stratify patients by PLP status at randomization minimizes the risk of having an underpowered study. The same tools can be used to enrich both the MCI and mild AD populations with PLPs to reduce SS requirements.
Combinatorial therapeutic effect of Environmental Enrichment and a Poly‐herbal formulation against amyloid‐beta induced Alzheimer’s disease in rodents
Authors: Rajendran Kayalvizhi , Krishnan Uma Maheswari , Chellappan David raj , Babu Aadhithyan
Published: December 2022

Background

Alzheimer’s disease (AD), a common form of dementia currently has no single disease‐modifying drug to halt disease progression. Environmental enrichment (EE) has emerged as an effective therapeutic strategy against various brain disorders. Our previous studies have revealed that the phytoformulation BN was effective in improving cognition and working memory in rodent models induced with cholinergic deficits. BN also inhibited tau hyperphosphorylation, increased dendritic arborization, and modulated AKT and MAPK pathways. In the present study, we propose to evaluate the combinatorial effect of BN and EE against AD.

Method

A rodent model of AD was created in Wistar rats through bilateral intra‐hippocampal injection of 100 µg/µL amyloid beta(1‐42). After ten days, the animals were randomly divided in to five groups (GII to GVI) and compared with normal animals (GI). The treatment regimen was commenced with GII acting as disease control, GIII receiving BN (844 mg/kg b.w), GIV receiving combined treatment of EE and BN, GV received only EE and GVI receiving the standard drug donepezil (4 mg/kg b.w.) for a period of 28 days. The cognition and spatial learning were assessed using behavioral studies. Gene and protein expression of key molecular targets were performed to gain insights into the molecular mechanism involved in the combination therapy. Amyloid plaque load was detected using thioflavin S, and dendritic morphology was studied using Golgi‐Cox staining. For EE, cages measuring 60×60×60 cm containing a running wheel, play tubes, ladder, balls, toys, and nesting material that are rearranged weekly, were used to study behavioral changes associated with cognitive stimulation.

Result

We found improved exploratory behaviour of the animals in EE when compared to their counterparts in normal cages. Other behavioral patterns like chewing, physical activity, sorting are significantly higher in animals subjected to the combination of EE and therapy when compared to animals treated in the conventional environment. The cognition and behavioral studies coupled with the histopathological results, gene and protein expression studies will help in establishing the molecular mechanism of the combination.

Conclusion

The results from this study open up new therapeutic directions involving environmental factors and multi‐targeted therapeutic agents against AD.
Cerebrovascular disease and dementia: exploring causal pathways
Authors: Sargurupremraj Muralidharan , Soumare Aicha , Bis Joshua C , Adams Hieab H.H. , Dufouil Carole , Milani Lili , Gudnason Vilmundur , van Duijn Cornelia M , Winsvold Bendik , Launer Lenore J. , Seshadri Sudha , Debette Stéphanie
Published: December 2022

Background

Cerebrovascular disease is increasingly recognized as playing a major role in the pathophysiology of dementia. We aimed to (i) explore the relation of genetically determined white matter hyperintensity burden (WMH) – a common MRI‐marker of covert cerebral small vessel disease (cSVD) – with risk of dementia and Alzheimer disease (AD); (ii) compare it with the relation of dementia/AD and genetically determined blood pressure (BP) and stroke, respectively a major risk factor and complication of WMH.

Method

Using a suite of two‐sample Mendelian randomization (MR) approaches we examined the association of genetic instruments for WMH, BP and stroke with AD, leveraging summary statistics of genome‐wide association studies. In addition to differentiating the causal effects of the exposure from shared effects of genetic instruments and outcome, we used multivariable approaches to estimate direct effects after accounting for potential confounders. Next, we used Cox proportional hazard and multi‐state models in 8 CHARGE cohorts to test the association of genetically determined WMH, BP and stroke with incident dementia (N = 10,034 cases) in a longitudinal setting and examined the relation of polygenic scores (PGS) for WMH, BP, and stroke with incident dementia (subtypes).

Result

Using two‐sample MR approaches we show strong evidence for a causal association of WMH with AD, with a marked increase (27.8%) in the direct effect of WMH on AD after accounting for confounding effects in a multivariable scheme. In population‐based longitudinal cohorts genetically determined WMH also showed nominal association with incident all dementia [HR: 1.01(1.00‐1.01)] and a WMH PGS was associated with increased risk of all dementia and AD [HR: 1.12(1.02‐1.23)], even after adjusting for interim stroke. In contrast, genetically determined stroke and BP showed (a trend to) an inverse association with AD using two‐sample MR, which was partly reversed (for BP) in a longitudinal setting.

Conclusion

Our results support a causal association of increasing WMH volume with dementia/AD risk, with indications that this may be specific to cSVD rather than reflecting the impact of related vascular phenotypes on dementia/AD, highlighting cSVD as an important target for prevention.
Nanoscale imaging of pT217‐tau in aged rhesus macaque: Trans‐synaptic propagation and seeding of tau pathology in entorhinal cortex
Authors: Datta Dibyadeep , Mentone SueAnn , Morozov Yury , van Dyck Christopher H , Arnsten Amy F. T.
Published: December 2022

Background

Tau pathology in Alzheimer’s Disease (AD) targets higher cortical circuits, with evidence that phosphorylated tau propagates from the entorhinal cortex (ERC) to “seed” pathology throughout the neuronal network. Recent discoveries indicate that tau phosphorylated at threonine 217 (pT217‐tau) can be captured in cerebrospinal fluid (CSF) and plasma as an early biomarker of ensuing disease. However, the role of pT217‐tau in brain tau pathology is unknown, especially as soluble tau species are dephosphorylated postmortem in humans. Rhesus macaques naturally develop the same qualitative pattern and sequence of tau and amyloid pathology, with neurofibrillary tangles comprised of paired helical filaments, identical to human AD. Perfusion fixation of monkey tissue preserves phosphorylation state and allows imaging of molecular location and interactions with nanometer resolution not possible in humans due to postmortem degradation. The current study examined the ultrastructural localization of pT217‐tau in layer II ERC of the aged rhesus macaques, focusing on potential evidence of propagation between neurons, and exposure to the extracellular space.

Method

We used immunohistochemistry paired with high spatial‐resolution immunoelectron microscopy (immunoEM) in aged rhesus macaques (18‐31 years) to localize pT217‐tau in the stellate cell islands in ERC layer II, which show the earliest signatures of tau pathology in AD.

Result

pT217‐tau immunolabeling was predominantly observed in postsynaptic compartments in macaque ERC layer II. pT217‐tau accumulated on the calcium‐storing smooth endoplasmic reticulum spine apparatus near axospinous asymmetric glutamatergic synapses in dendritic spines. We observed extensive, trans‐synaptic pT217‐tau trafficking between interconnected neurons within omega‐shaped bodies in ERC layer II, specifically near excitatory, but not inhibitory synapses. Within dendritic shafts, pT217‐tau aggregated on microtubules often in concordance with autophagic vacuoles indicative of neurite dystrophy.

Conclusion

pT217‐tau accumulates in ERC layer II subcompartments known to be the earliest to show pathology in humans. The data provide the first evidence of pT217‐tau trafficking between neurons to “seed” tau pathology in higher brain circuits, potentially interfacing with the extracellular space to become readily accessible and captured in CSF and blood as a robust AD biomarker. Illuminating patterns of neurodegeneration with pT217‐tau could potentially guide earlier intervention of therapeutics that might mitigate tau hyperphosphorylation in AD.
Case of Dementia with Lewy Bodies in Young Patient with Family History
Authors: Singh Neeraj , Ayyalu Tanesh , Fredrick Jason
Published: December 2022

Background

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder characterized by cognitive decline, fluctuating attention, visual hallucinations, and sleep disorders, sometimes with signs of parkinsonism. Pathological evaluation reveals deposition of abnormally metabolized alpha‐synuclein, termed Lewy bodies. Clinical signs of DLB may be misdiagnosed in young patients with coexisting psychiatric disorders. A 43‐year‐old left‐handed man with a history of chronic paranoid schizophrenia, controlled with haloperidol, paroxetine, quetiapine, and clonazepam, presented with a 3‐year history of declining short‐term memory and concentration. He had a twin brother who was diagnosed with DLB and passed away at 40 years of age.

Methods

The patient was evaluated with serum laboratory tests to evaluate for metabolic abnormalities, infection, and heavy metal toxicity, including complete blood count, comprehensive metabolic panel, vitamin B12, folate, thyroid stimulating hormone, copper, and zinc. MRI Brain and subsequent PET‐FDG Brain were also conducted.

Results

The results of the serum laboratory tests were all normal. MRI Brain was notable for bilateral parieto‐occipital atrophy and minimal chronic microvascular changes. PET‐FDG Brain revealed hypometabolism in bilateral parietal and occipital regions, with a cingulate island sign, indicative of advanced dementia with Lewy bodies.

Conclusion

Dementia with Lewy bodies is a form of dementia that can sometimes present at an early age, and can be associated with psychological comorbidities and genetic risk factors. Further study of this case will include screening for mutations in the GBA gene, which encodes the enzyme beta‐glucocerebrosidease, which is the most frequent genetic association with dementia with Lewy bodies. Counseling on diagnosis and prognosis has been provided to the patient and his family, and he is being managed with rivastigmine 1.5mg twice daily to help slow down cognitive decline.
Causal Inference in Unrepresentative Databases: An Analysis of Vitamin E Supplementation in the National Alzheimer’s Coordinating Center Uniform Dataset
Authors: Morgan Olivia M. Bernstein , Vegetabile Brian G. , Gillen Daniel L. , Grill Joshua
Published: December 2022

Background

Self‐selection into research studies can lead to samples that are unrepresentative of the target population. For example, the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set is often used to identify risk factors of Alzheimer’s disease and overrepresents highly educated and non‐Hispanic White participants, relative to the US population. Sampling weights that are related to the self‐selection of enrolling in the NACC database can be used to estimate causal effects in the US population of older adults. We applied this strategy to estimate the effect of vitamin E supplementation on functional activities using NACC data and estimated sampling weights as proof of concept. A meta‐analysis found mixed evidence about the effect of vitamin E on functional outcomes in cognitively normal older adults (Browne et al. 2019).

Methods

We used baseline data for NACC participants who enrolled from 2005‐2021, were cognitively normal, and 65 or older. The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA‐funded ADCs. We estimated the probability of self‐selection into NACC relative to a nationally representative survey. We used the corresponding sampling weights to estimate weighted propensity scores and weighted propensity‐adjusted estimates of the effect of vitamin E supplementation on the Functional Activities Questionnaire (FAQ) and compared the results to unweighted models.

Results

After excluding 809 participants missing the FAQ, there were 14,358 participants. When incorporating sampling weights to obtain inference about the US population, we estimated that participants who take vitamin E supplements have a 0.29 point lower (95% CI: ‐0.54, ‐0.04) FAQ score, on average, compared to participants who do not. When failing to account for sampling bias and omitting sampling weights, we estimated that they have a 0.01 point lower (95% CI: ‐0.11, 0.09) FAQ score, on average (see figure).

Conclusion

When accounting for sampling bias we estimated that participants who take vitamin E supplements perform better on the FAQ compared to those who do not, but this effect was attenuated when failing to account for sampling weights. Incorporating estimated sampling weights allows for better isolation of causal effects in the population of interest.
Retromer subunit, VPS29, regulates vacuolar‐type ATPase and lysosomal acidification in the aging brain
Authors: Ye Hui , Bagchi Pritha , Wu Timothy , Dammer Eric B , Seyfried Nicholas T. , Shulman Joshua M
Published: December 2022

Background

The retromer, including VPS35, VPS26, and VPS29, is an evolutionarily conserved protein complex that retrieves cargoes from the endosome to the trans‐Golgi network or plasma membrane. Retromer regulates Tau phosphorylation and pathogenic processing of the amyloid precursor protein, both of which are neuropathological hallmarks of Alzheimer’s disease (AD). Previously, we found that loss of VPS29 in Drosophila causes progressive lysosomal dysfunction during aging, but the underlying molecular mechanism remains elusive.

Method

To investigate the molecular events in Drosophila heads caused by loss of Vps29, we performed quantitative proteomics on Vps29 mutants and age‐matched control animals, and identified 480 significant, differentially expressed proteins. To study the lysosomal acidity in fly Vps29 mutants, we neuronally expressed LAMP1‐GFP, a pH‐sensitive indicator that is localized to the lysosomal lumen. To evaluate the potential translational relevance of our findings, we knocked down retromer subunits in mammalian cell culture and examined levels of vacuolar‐type ATPase (v‐ATPase) subunits. We also interrogated available human postmortem brain proteomic data from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP).

Result

Unbiased proteomics from VPS29 mutant flies revealed a sharp decline in subunits of the v‐ATPase, a multimeric proton pump that is primarily responsible for lysosomal acidification. Importantly, we obtained consistent evidence from mammalian cell culture. In aged Vps29 mutant fly brains, the LAMP1‐GFP pH sensor indicated impaired lysosomal acidification. Lastly, based on ROSMAP human brain proteomics, we found that VPS29 protein levels were significantly coexpressed with other proteins implicated in energy‐coupled proton transmembrane transport, including multiple subunits of the conserved v‐ATPase.

Conclusion

Our findings highlight a conserved role for retromer in regulating the v‐ATPase, possibly contributing to lysosomal acidification. Drosophila is a powerful model system for functional dissection of the retromer in the mammalian brains, including in AD pathogenesis.
Mitochondrial genome abundance is associated with Alzheimer’s disease neuropathological burden and cognitive function
Authors: Harerimana Nadia V. , Paliwal Devashi , Romero Carmen , Bennett David A , Pa Judy , Swerdlow Russell H , Goate Alison , Andrews Shea J
Published: December 2022

Background

Mitochondrial DNA copy number (mtDNAcn) is a measure of mitochondrial genome abundance that is associated with age related diseases. mtDNA can also carry mutations that affect all copies of the mtDNA or only a fraction of the mtDNA molecules (heteroplasmy, mtHz) within an individual cell. To evaluate the role of mitochondrial dysfunction in Alzheimer’s disease (AD) we investigated the association of mtDNAcn levels and mtHz burden with AD neuropathological change and cognitive function.

Methods

Neuropathology and genomic data were obtained from 1,381 non‐Hispanic white postmortem brain tissue samples from the Accelerating Medicines Partnership for Alzheimer’s disease (AMP‐AD). neuropathological AD was based on burden of amyloid plaques (CERAD) and neurofibrillary tangles (Braak). Relative mtDNAcn was estimated as the ratio of mtDNA to nuclear DNA, and mtHz burden was defined as the number of mtHz variants. The association of mtDNAcn and mtHz with ADNC was evaluated using logistic regression, and amyloid and tau burden using ordinal logistic regression, adjusting for mitochondrial haplogroup, age at death, sex, APOE, post‐mortem interval, study, and tissue. The association of mtDNAcn and mtHz with cognitive performance was evaluated using linear regression (n=785). As mtDNAcn levels estimated from bulk tissue can be influenced by cell type proportion, we conducted a sensitivity analysis adjusting for neuronal cell type proportion estimated from RNAseq (n=494).

Results

Higher mtDNAcn was associated with reduced risk of neuropathological AD and tau burden, but not with amyloid burden, and with higher cognitive performance for perceptual speed, episodic memory, working memory, global cognition, and semantic memory. In sensitivity analyses adjusting for neuronal cell type proportion, mtDNAcn remained significantly associated with neuropathological AD, perceptual speed, and working memory. mtHz was not significantly associated with neuropathology or cognition.

Conclusion

Increased mtDNAcn levels estimated from postmortem brain tissue are associated with reduced risk of AD neuropathology and higher cognitive performance. This suggests that mitochondrial genome abundance is associated with AD pathogenesis, potentially by impairing mitochondrial bioenergetics and thereby impacting neuronal or microglia cell function. Drugs that upregulate total mitochondrial genome abundance or boost mitochondrial mass may ameliorate AD pathogenesis.
Assessment of gray matter microstructure and synaptic density in Alzheimer's Disease: a multimodal imaging study with DWI and SV2A PET
Authors: Salardini Elaheh , Silva‐Rudberg Jason A , O'Dell Ryan S. , Chen Ming‐Kai , Ra Jocelyn , Georgelos Jamie K , Morehouse Mackenzie R , Melino Kaitlyn P , Nabulsi Nabeel B. , Huang Yiyun , Carson Richard E. , van Dyck Christopher H , Mecca Adam P
Published: December 2022

Background

Diffusion weighted imaging (DWI) is proposed to show alterations to microscopic barriers (O'Donnell, et al. 2011) associated with neurodegeneration (Jacobs, et al. 2013). Positron emission tomography (PET) imaging has also been used to measure synaptic density. Previously, we have shown that synaptic density is lower in Alzheimer's Disease (AD) participants (Mecca, et al. 2020) and is correlated with cognitive performance in patients with AD. Here, we aim to investigate the relationship between DWI metrics and synaptic density in gray matter in the hope of better understanding of AD neurobiology.

Method

Thirty‐four amyloid positive participants with clinical diagnosis of AD and 18 amyloid negative cognitively normal (CN) participants were included in this study. Early AD‐affected regions (entorhinal cortex, hippocampus, posterior cingulate, and precuneus) were chosen as the primary region of interest (ROI). Synaptic density was measured using [11C]UCB‐J PET where the distribution volume ratio in ROIs was computed using SRTM2 with cerebellum as reference region. Average axial diffusivity (AxD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) within each ROIs was computed using Freesurfer 6. Between group comparisons were performed using an unpaired t‐test. Association between gray matter DWI metrics and synaptic density was assessed using univariate regression analyses.

Results

AxD was significantly higher in AD participants in entorhinal cortex and hippocampus bilaterally as well as right posterior cingulate and left precuneus. FA was significantly lower in left hippocampus, and significantly higher in right hippocampus and right posterior cingulate in AD participants. MD was significantly higher in AD participants in bilateral entorhinal cortex, left hippocampus and left precuneus. RD was significantly higher in AD participants in left precuneus, bilateral entorhinal cortex and hippocampus. Within AD participants, synaptic density was inversely correlated with AxD, MD, and RD in the entorhinal cortex and hippocampus bilaterally and positively correlated with FA in the left precuneus. These associations were absent in the CN group.

Conclusion

We found that DWI metrics had significant correlation with synaptic density in Early AD‐affected regions in participants with AD, but not in CN participants. We hypothesize that DWI outcome alterations is reflective of gray matter microstructural changes related to synaptic loss.
The effect of age on mnemonic discrimination is fully mediated by posterior cerebral artery‐defined white matter hyperintensities
Authors: Rizvi Batool , Sathishkumar Mithra , Larson Myra S , Tustison Nicholas J. , McMillan Liv , Greenia Dana E. , Corrada Maria M. , Kawas Claudia H. , Yassa Michael A.
Published: December 2022

Background

Previous work has observed a decline in memory performance with age on mnemonic discrimination tasks (MDT). Other studies have recognized the contributions of white matter hyperintensities (WMH), a marker of cerebrovascular disease, on age and Alzheimer’s disease‐related memory decline. Here, we asked whether WMH, defined within vascular territories, particularly the posterior cerebral artery (PCA) defined territory, would mediate the association between age and MDT performance.

Method

A sample of 120 older adults (mean age (SD) = 76.6 (10.43) years, age range: 59‐98 years, 74 (61.7%) females) were included in these analyses. Regional WMH volumes were derived from T2‐FLAIR (Figure 1A) images using ANTs, a vascular territory atlas (Figure 1B) and manual editing. The MDT was administered to assess episodic memory and pattern separation ability within both the object (MDT‐O) and spatial (MDT‐S) domains. Adjusting for sex and education, we tested for associations among age, regional WMH volumes, MDT‐S, and MDT‐O scores, correcting for multiple comparisons. Results were then used to assess the mediating role of regional WMH on the relationship between age and MDT. Lastly, we compared the accuracy of the different vascular territory WMH volumes, along with total WMH volume, in classifying cognitive impairment (MCI, QCI, CIND) using area under the receiver operating characteristic curve (ROC).

Result

Age was associated with MDT‐S (β=‐0.247, p=0.005), but not MDT‐O performance (β=‐0.130, p=0.177). Only PCA‐defined WMH volume was associated with MDT‐S (β=‐0.252, p=0.005) and MDT‐O (b=‐0.229, p=0.016). PCA‐defined WMH fully mediated the association between age and MDT‐S (indirect effect: β=‐0.001, 95% CI (‐0.003, ‐0.001); Figure 2A). Similarly, PCA‐defined WMH fully mediated the association between age and MDT‐O (β=‐0.001, 95% CI (‐0.002, ‐0.003); Figure 2B). PCA‐defined WMH volume more accurately classified cognitively impaired from non‐impaired (AUC=0.780, p<0.001; Figure 3) compared with total WMH (AUC=0.624, p=0.113), ACA‐defined WMH volume (AUC=0.618, p=.130) or MCA‐defined WMH (AUC=0.592, p=0.237).

Conclusion

PCA‐defined WMH mediate the relationship between age and memory performance and is a better diagnostic of cognitive impairment than whole brain or other vascular territory WMH volumes. This study demonstrates that defining WMH within vascular territories provides a useful way to characterize the impact of aging on memory impairment.
Qrater: collaborative imaging quality control tool
Authors: Fernandez‐Lozano Sofia , Dadar Mahsa , Morrison Cassandra , Manera Ana Laura , Fonov Vladimir S , Collins Louis D
Published: December 2022

Background

Quality control (QC) is particularly important in vulnerable populations like patients with dementia where movement artifacts as well as registration failures may be more prevalent. From our need to review the quality of tens of thousands of raw MR images and reviewing the steps of our pre‐ and post‐processing pipelines, we developed Qrater. Qrater is a web‐based application installed centrally on a server where our data is stored. We can then rate the images and access the database of our team’s stored ratings (QC status and potential comments for each image).

Method

In Qrater the images are uploaded as datasets that can be restricted to specific users (Fig. 1). Each image is viewed and rated with available features such as a magnifying glass, seeing other users’ ratings, adding specifying comments, moving between images, and rating with key bindings to store QC outcomes other than pass/fail/warning (Fig. 2.). Looking for a specific image or rating is made easier by the search and sorting features (Fig. 3). Four experienced researchers rated three different datasets of MRI (A: 1275 unprocessed T1w brain images; B: 1623 unprocessed T1w brain images; C: 3000 preprocessed T1w brain images non‐linearly registered to a standard template). We looked at timing from the ratings’ timestamps to determine how much time it took to rate the datasets. All analyses were done in R v 4.1.

Result

On average, it took between 10 and 25 seconds to rate each image (14.2 s dataset A, 25.5 s dataset B and 14.1 s dataset C. Figure 1); less than 10 seconds to mark a clearly failed image for both raw acquisition and registration tasks, while the more questionable images (marked as Warning) took between one and two minutes (Table 1, Fig. 4).

Conclusion

Our team has found Qrater’s usability to be a significant improvement over previous quality control methods. The built‐in SQL database supports thousands of images without affecting its performance, and the web‐based interface enables remote QC. Since Qrater belongs to the initiative towards a more open and reproducible science, the code is currently available for download in GitHub [https://github.com/soffiafdz/Qrater].