bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic characterization of small vessel pathology in PSEN1 E280A familial Alzheimer’s disease
Authors: Littau Jessica Lisa , Amri Yassir El , Villalba‐Moreno Nelson David , Shafiq Mohsin , Lopera Francisco , ‐Lanau Andres Villegas , Sepulveda‐Falla Diego 
Published: December 2023

AbstractBackgroundVascular pathology is a main contributor to Alzheimer’s disease (AD) progression and severity. We have previously characterized vascular pathology in the PSEN1E280A Colombian kindred. In postmortem analyses we identified that the occipital cortex (OC) is the most affected region by small vessel disease (SVD), including other cortical areas and basal ganglia. Interestingly, frontal cortex (FC) is spared from tau pathology in protected PSEN1E280A cases, while the OC is not. Here we study the proteome of isolated vessels from frontal and occipital cortices to identify differences in molecular pathways.MethodApproximately 400 mg of FC and OC of postmortem brain tissue from PSEN1E280A familial AD (FAD, n = 10), sporadic AD (SAD, n = 10) and controls (HC, n = 5) were homogenized, centrifuged at 2000 g / 5 minutes before using gradient centrifugation at 10000 g / 15 minutes with dextran to receive the microvessel containing pellet which was retrieved and resuspended in lysis buffer for tandem mass tag (TMT) proteomics. Proteomics spectral data were matched to peptide sequences in the human UniProt protein database using the MaxQuant software package. The MaxQuant output files were analysed by MSstatsTMT using R software for statistical analysis. clusterProfiler package was used to perform Gene Ontology enrichment analyses.ResultMicrovessels isolated from AD OC showed 1597 significantly dysregulated proteins when compared to controls, while FC showed 523. FAD showed the majority of upregulated proteins in FC (181 > 88 in SAD), and OC (428 > 84). This pattern was similar in downregulated proteins in the OC (391>171), but not in the FC (106<156) (Fig. 1A). The comparison between FAD cases and controls was the only one that identified a variety of biological processes (BP) during Protein set enrichment analysis. Notably, FAD FC showed upregulation of BP associated to vessel proliferation (Fig. 1B), while the OC showed downregulation of BP associated to immune system and mRNA regulation (Fig. 1C).ConclusionWe have identified the OC as a critical region of FAD pathology. Proteomic analysis of isolated microvessels from this region point towards a more deleterious profile while the FC microvessel proteome indicates an earlier stage of SVD pathology.
Racial and Ethnic Differences in Plasma Biomarker Eligibility in a Preclinical Alzheimer’s Disease Trial
Authors: Molina‐Henry Doris P. , Raman Rema , Liu Andy , Langford Oliver , Johnson Keith A. , Shum Leona K , Glover Crystal M , Aisen Paul S. S , Dhadda Shobha , Irizarry Michael C. , Sperling Reisa A. , Grill Joshua D. 
Published: December 2023

AbstractBackgroundIn Alzheimer’s disease (AD) trials, differential screen failure due to cognitive and biomarker requirements may contribute to underrepresentation of racially and ethnically minoritized groups. The AHEAD 3‐45 Study (NCT04468659) is an ongoing program testing lecanemab at the stage of preclinical AD that utilizes plasma biomarker prescreening, acquired before cognitive, clinical, and medical history eligibility assessments, to enrich for participants likely to qualify based on amyloid PET eligibility criteria.MethodsWe examined the frequency of plasma amyloid biomarker eligibility among racial and ethnic groups in the AHEAD Study. We assigned participants ages 55‐80 to mutually exclusive groups: Hispanic Black (HB), Hispanic White (HW), Non‐Hispanic Asian (NHA), Non‐Hispanic Black (NHB), and Non‐Hispanic White (NHW). We used univariate logistic regression models to explore group differences in screen failure rates as determined by an algorithm that includes the plasma Aβ 42/40 ratio, age, and APOE status. The algorithm indicates an adequately high probability of elevated brain amyloid (>20 centiloids). We further explored whether APOE ε4 status (carrier vs non‐carrier) contributed to group differences.ResultsAmong 4274 participants undergoing plasma screening, 59 (1.4%) were HB, 622 (14.6%) were HW, 74 (1.73%) were NHA, 329 (7.7%) were NHB, and 3190 (74.6%) were NHW. Screen failure rates were 86% for HB, 76% for HW; 80% for NHA; 77% for NHB, and 62% for NHW. Using NHW participants as a reference group, we observed increased odds of screen failure among all other groups (HB OR = 4.0 95% CI 2.0, 9.1; HW OR = 2.0 95% CI 1.6, 2.4; NHA OR = 2.5 95% CI 1.4, 4.5; NHB OR = 2.1, 95% CI 1.6, 2.7). Observed differences were consistent across APOE ε4 carriers and non‐carriers.ConclusionDifferential rates of amyloid eligibility were observed despite the lack of systematic sample bias due to clinical or cognitive requirements observed in previous studies. Potential explanations for these observations include differences in clinical trial access, incidences of elevated amyloid, needed cutoffs for biomarker assays, and confounding due to comorbidities or other unmeasured covariates.This work is supported by a public‐private partnership between Alzheimer’s Clinical Trial Consortium (U24 AG057437) and Eisai.
Glucose intake is influencing the concentration of AD‐related plasma biomarkers in healthy adults
Authors: Grötschel Lana , Huber Hanna , Ashton Nicholas J. , Schieren Alina , Weinhold Leonie , Schmid Matthias , Coenen Martin , Blennow Kaj , Stehle Peter , Zetterberg Henrik , Simon Marie‐Christine 
Published: December 2023

AbstractBackgroundBlood biomarker analyses are seen as a great aid to early diagnose and confirm underlying Alzheimer’s disease (AD) pathology. Developing evidence suggests that certain confounders need to be considered which may affect the reliability of biomarker results, e.g., chronic kidney disease. However, little is known with respect to potential confounding effects of energy/nutrient intake on these biomarkers. Thus, we aim to study the short‐term effects of oral glucose intake in healthy, obese adults.Method111 participants (60±7y, BMI 31±4kg/m2, 47 males) ingested 300ml of a glucose syrup (75g glucose, Accu‐Chek, Roche). Neurofilament light, glial fibrillary acidic protein [GFAP], amyloid‐β 42/40 ratio, phosphorylated tau ([p‐tau] 181 and p‐tau 231) were measured in fasting (0 minutes) and postprandial blood samples collected 15, 30, 45, 60, 120 and 180 minutes after ingestion of the glucose syrup using ultra‐sensitive Single molecule array assays. Additionally, a fasting (control) group (n = 26) was followed over the same time period. Statistical analysis was done using polynomial spline of degree 3 to test for differences in parameter progression over time within and between groups.ResultIn both groups, all biomarkers changed significantly over time (glucose group: all p<0.0001, fasting group all p<0.05) compared to baseline (0 minutes). The changes to baseline in GFAP were significantly different after glucose ingestion compared to the fasting state (p<0.0001). The GFAP level decreased in the early postprandial phase (until 60 minutes) and subsequently increased in the late postprandial phase.ConclusionOur results suggest that plasma biomarkers for AD‐related pathologies are influenced by the individual nutritional status (prolonged fasting, postprandial situation). This should be considered when using AD‐related biomarkers for screening and diagnostic purposes.
Cognitive sequealae of COVID‐19 is not predicted by SARS‐CoV‐2 variants
Authors: de Erausquin Gabriel A. , Zwir Jorge Igor , Snyder Heather M , Gonzalez‐Aleman Gabriela , Zamponi Hernan P. , Figueredo‐Aguiar Mariana , Fumagalli Emiliano , Blangero John , Yécora Agustín , Vaca Fabiana , Kukoc Gabriela , Dominguez Maria Eugenia , Calvó Maria , Padilla Eduardo G , Guerrero Gonzalo , Habes Mohamad , Fox Peter T , Seshadri Sudha ,   Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2
Published: December 2023

AbstractBackgroundThe long term sequelae of COVID‐19 in older adults are only beginning to be clarified, and its predictors and underlying molecular mechanisms may shed light on the relationship between viral infections and Alzheimer’s disease and related dementia.MethodA prospective cohort of 874 older adult Amerindians from Argentina with COVID‐19 illness confirmed by PCR of nasal swabs as well as controls, was established during the first year of the COVID‐19 pandemic. We obtained data on the severity of the acute illness, as well as extensive neuropsychiatric and cognitive assessments, neurological exams (including quantitative hyposmia/anosmia), plasma for biomarkers and preliminary brain MRI images using the ADNI‐3 protoco (n = 300)l,and whole genome sequencing (n = 300). Isolates from SARS‐CoV‐2 were obtained by the provincial Direction of Epidemiology and sequenced by the national Ministry of Health. Variants of interest/concern were allocated to each case on the basis of the prevalent community isolate at the time of confirmed positive PCR. A deep learning strategy was used to identify predictive factors of cognitive and clinical outcomes.ResultFour distinctive cognitive profiles were identified. Greater cognitive impairment was associated with older age (p = E−9), worse acute COVID‐19 illness (p = 0.008), unvaccinated status (p = E−7), and severity of anosmia (p = E−5). SARS‐CoV‐2 variant was associated with severity of acute illness ((p = E−6) but notably not with cognitive impairment. Preliminary analysis of genomic and brain imaging data will be presented.ConclusionOur data strongly suggest that all SARS‐CoV‐2 variants of interest up to the omicron wave seem equally likely to result in cognitive impairment in older adults, modulated by the severity of the acute illness.
Development and Validation of the Modified Neuropsychological Test Battery (PmNTB) in the Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER)
Authors: Papp Kathryn V. , Farias Sarah Tomaszewski , Ngandu Tiia , Sachs Bonnie C. , Chan Michelle L , Krueger Kristin R , York Michelle , Lee Athene KW , Hartman Elizabeth , Thro Amber Adkins , Caudle Brad A , Howard Marjorie , Leng Xiaoyan , Snyder Heather M , Carrillo Maria C. , Whitmer Rachel A. , Espeland Mark A. , Baker Laura D 
Published: December 2023

AbstractBackgroundThe U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) will determine whether interventions that simultaneously include multiple risk reduction strategies can protect cognitive health in older adults. The primary outcome, a global cognitive composite score derived from the POINTER‐Modified Neuropsychological Test Battery (PmNTB), was developed to allow for outcome harmonization with its forerunner, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and other large trials (e.g., A4, EXERT). Here we describe the PmNTB and its initial validation in the baseline U.S. POINTER sample.MethodU.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two interventions varying in intensity and format, in older adults at increased risk for cognitive decline and dementia. The PmNTB includes performance from 7 cognitive tests and is computed as the mean of three domain‐specific composites: Episodic Memory, Processing Speed, and Executive Function. The Episodic Memory Composite includes Free and Cued Selective Reminding Test, Story Recall, and Visual Paired Associates. The Processing Speed Composite includes Trail Making Test (TMTA) and Digit Symbol Substitution Test. The Executive Function Composite includes Number Span, Word Fluency, and TMTB. PmNTB was assessed in relation to age, clinical status (Clinical Dementia Rating‐CDR), and other cognitive composites able to be computed in the current sample using overlapping measures (i.e., FINGER NTB, Preclinical Alzheimer’s Cognitive Composite‐PACC‐5).Result2094 participants completed the baseline assessment (mean age = 68.2±5.2 years; 68.8% female, 69.1% non‐hispanic white, mean MMSE = 28.9± 1.3). Global CDR was 0 for 79.5% of participants, and 0.5 for 20.5% of participants. After adjusting for education, race, ethnicity, and sex, each additional year in age was associated with a drop in PmNTB z‐score by ‐0.064 (95%CI = ‐0.071,‐0.056, p<0.001). Likewise, global CDR = 0.5 (questionable dementia) was associated with a lower PmNTB score (z = ‐0.549) compared with global CDR = 0 (‐0.134 z‐scores). PmNTB correlated with the FINGER NTB (r = 0.858, p<0.001) and the PACC‐5 (r = 0.876, p<0.001).ConclusionThe PmNTB is a valid measure of cognitive functioning, capturing age‐related cognitive decrements and is associated with clinically relevant, functional outcomes. It also exhibits convergent validity with established cognitive outcomes.
Six‐month risk of non‐traumatic intracranial hemorrhage in cognitively impaired patients following Covid‐19 infection
Authors: Gillis Cai , Wang Nasha , Montenigro Philip H. , Maserejian Nancy Nairi 
Published: December 2023

AbstractBackgroundStudies suggest dementia patients have higher rates of non‐traumatic intracranial hemorrhage (nt‐ICH) compared to cognitively‐unimpaired peers. Recent studies also suggest increased risk of nt‐ICH, following infection with Covid‐19 in the general population. However, the risk of nt‐ICH following Covid‐19 infection in cognitively‐impaired individuals is currently unknown.MethodUsing US electronic health records ICD codes, we matched Alzheimer’s disease (AD), dementia, and mild cognitive impairment (MCI) cases with a history of Covid‐19 to similarly cognitively impaired controls without Covid‐19 history and examined incidence of nt‐ICH over six‐months following infection. Cases and controls were propensity score matched on age, sex, race, ethnicity, time since cognitive‐diagnosis, anticoagulant use, antiplatelet use, and 37 comorbidities. Analyses focused on the first year of the pandemic in 2020, prior to availability of at‐home tests and vaccines, to reduce misclassification bias. Individuals with prior history of nt‐ICH, traumatic ICH, or stroke were excluded to focus on incident nt‐ICH. Cox proportional hazard models compared risk between those with and without Covid‐19.ResultOur sample included 2,287 AD cases with Covid‐19 matched to 6,861 AD controls; 5,726 dementia cases matched to 17,178 dementia controls; and 807 MCI cases matched to 2,419 MCI controls. The incidence of nt‐ICH following Covid‐19, among AD cases, was 12.53/1,000 person‐years (95% CI: 7.66‐19.36) vs. 4.16/1,000 person‐years (95% CI: 2.51‐6.50) in AD patients without Covid‐19; HR = 3.1 (95% CI: 1.7, 5.8), p = 0.0004. Similarly in dementia patients, Covid‐19 increased the risk by 3.0 times (95% CI: 1.8, 4.7), p<0.0001. The incidence in dementia Covid‐19 cases was 8.48/1,000 person‐years (95% CI: 5.91, 11.80) vs. 2.97/1,000 person‐years (95% CI: 2.07, 4.13) in dementia patients without a history of Covid‐19 over the study period. The incidence in MCI patients with a history of Covid‐19 was 5.03/1,000 person‐years (95% CI: 1.37, 12.87), vs. 1.56/1,000 person‐years (95% CI: 0.32, 4.57) in MCI controls, but risk was not significantly different; HR = 3.4 (95% CI: 0.8, 15.0), p = 0.11.ConclusionAlthough nt‐ICH was rare among cognitively impaired patients following Covid‐19 infection in 2020, the risk over 6‐months in AD and dementia cases was approximately 3 times higher than controls without a history of Covid‐19.
Post‐mortem MRI white matter hyperintensities are associated with cortical astrocytopathy and water channel expression in the oldest‐old
Authors: Roese Natalie E , Hurworth Justin , Krajbich Victoria , Schwartz Daniel , Lahna David , Wall Rachel C , Woltjer Randy L , Silbert Lisa C 
Published: December 2023

AbstractBackgroundCerebrovascular small vessel disease, a common cause of cognitive impairment in older individuals, is characterized by the presence of MRI white matter hyperintensities (WMH). Our previous MRI‐targeted histopathological studies have found WMHs and the surrounding NAWM penumbra to be associated with glial markers. This study aims to assess the relationship between cortical markers of glial dysfunction and post‐mortem (PM) MRI WMH.MethodLeft brain hemispheres were obtained from 45 Oregon Alzheimer’s Disease Research Center subjects >/ = 80 years of age without significant AD pathology. Intact and sliced hemispheres were scanned at 7T MRI. MRI scans were used to target histological sampling. Slides were stained for glial fibrillary acid protein (GFAP), ionized calcium binding adapter molecule‐1 (IBA1), aquaporin‐1 (AQP1), aquaporin‐4 (AQP4), vimentin and amyloid‐beta (ABETA). Slides were co‐registered to MRI. Tissue masks were hand‐drawn to delineate white matter and cortex. Cortical ROIs were quantified for mean pixel value (AQP1, AQP4, GFAP, and Vimentin) or area coverage (IBA1, ABETA). Cassettes with no local WMH were compared with those in the top third of slide WMH coverage (187 cassettes). Global WMH burden was dichotomized at the mean. Linear mixed‐effects models regressed stain quantification on local WMH (in slide) and global WMH burden, with a random effect for staining batch (levels = 4). The final model controlled for age at death and ABETA expression within a slide. Interactions between local and global WMH were included where appropriate.ResultHigh local WMH burden was associated with greater cortical vimentin (p = 0.036), GFAP (p = 0.066), and AQP4 (p = 0.004), while high global WMH burden was associated with greater IBA1 (p = 0.034) and AQP1 (p = 0.071). An interaction was identified between local and global WMH burden for AQP1 (p<0.10), such that in subjects with high global WMH burden, high local WMH burden was associated with higher AQP1. Greater local cortical ABETA was associated with cortical AQP1 (p = 0.004) expression.ConclusionIn oldest‐old individuals without significant AD pathology, high local and global PM‐MRI WMH burden is associated with cortical astrocytopathy, including increased water channel expression and inflammation. Findings implicate WMH as a state marker of widespread cortical pathology that may confer increased vulnerability to cognitive decline with advanced age.
Amygdala tau deposition best discriminates between stages of memory impairment
Authors: Huyghe Lara , Gérard Thomas , Colmant Lise , Salman Yasmine , Malotaux Vincent , Lhommel Renaud , Dricot Laurence , Ivanoiu Adrian , Quenon Lisa , Hanseeuw Bernard J 
Published: December 2023

AbstractBackgroundThe recent development of positron emission tomography (PET) radiotracers for tau aggregates allows quantifying the regional tau burden in‐vivo. We aimed to investigate the associations between regional tauopathy and episodic memory outcomes in the AD spectrum from clinically normal to the dementia stage.MethodWe recruited 111 participants between 2019 and 2023 at the Memory Clinic of Saint‐Luc University Hospital. Each participant underwent [F18]‐MK6240 tau‐PET, 3DT1 MRI, cognitive assessment, and either lumbar puncture or [F18]‐Flutemetamol PET for amyloid status. Tau burden was quantified using Freesurfer by referring to the Desikan‐Kiliany lobe cortical parcellation, as well as in several medio‐temporal regions (MTL; i.e., entorhinal cortex, amygdala, hippocampus). Memory was assessed using three Z‐scores from the FCSRT: Sum of Free Recall (SFR), Sum of Total Recall (STR), and Sum of Delayed Free Recall (DFR). The average of these scores forms the Memory Composite Score (MCS). Participants were classified in three groups (Table 1): amyloid‐negative clinically normal participants (n = 44); non‐demented participants with AD pathology (early AD, n = 45); and AD dementia participants (n = 22). Based on their SFR and STR scores, subjects were also classified as having retrieval and/or encoding memory deficits according to a Stage of Objective Memory Impairment (SOMI) classification, inspired from Grober and colleagues (2018). Analyses were corrected for multiple comparisons.ResultIn early AD, SFR and DFR correlated with tauopathy in the bilateral entorhinal cortex (EC) and amygdala (Fig.1). MCS correlated with tauopathy in the bilateral amygdala, and the right frontal lobe. Tau levels did not correlate with STR in any regions. Moreover, MTL tauopathy differed between SOMI stages: Specifically, amygdala tauopathy gradually increased with retrieval deficits (SOMI1‐2) and encoding deficits (SOMI3‐4). In contrast, tauopathy in the EC, the temporal lobe, and the parietal lobe was elevated in all participants with memory deficits, but did not distinguish between retrieval and encoding deficits (Table 2).ConclusionTauopathy in the MTL ROIs is predictive of retrieval deficits in early stage of AD. SFR is a more sensitive measure of this early decline compared to STR. Amygdala tauopathy differs between patients with retrieval and encoding deficits.
Detection of Early Alzheimer’s disease at AdventHealth: A Davos Alzheimer’s Collaborative flagship site
Authors: Baldivieso Valeria , Erickson Kirk I. , Smith Steven R. , Pratley Richard E. , Baksh Magda R. , Shepherd Gayle , Lopez Janice , Jain Shivangi , Selzler Katherine J. , Murray James F , West Tim , Ortega Julia , Coppinger Justine , Venkatesh Venky , Monane Mark , Braunstein Joel B. 
Published: December 2023

AbstractBackgroundEarly identification of Alzheimer’s disease (AD) is critical for disease‐modifying therapies. The Davos Alzheimer’s Collaborative flagship program tested the feasibility of implementing a digital cognitive assessment (DCA) followed by a blood biomarker (BBM) for early detection of cognitive impairment (CI).MethodIndividuals ≥65 years without dementia were approached via their primary care provider (PCP) or through direct‐to‐consumer (DTC) social media. After consenting, participants completed the Cogstate Brief Battery (CBB) DCA. Participants with an abnormal or borderline CBB score were offered the Montreal Cognitive Assessment (MoCA) and the PrecivityAD® blood test, a CLIA‐certified laboratory developed test that uses mass spectrometry to analyze biomarkers to identify brain amyloid plaques (reported by the Amyloid Probability Score‐APS) in individuals with CI.ResultOver 2300 participants expressed interest. Of 2001 eligible, 1076 (96% social media, 4% PCP) e‐consented. 742 completed the CBB of which 211 (28%) were borderline, 113 (15%) abnormal, and 418 (56%) were negative for CI. Of the 324 with borderline or abnormal CBB scores, 219 (67%) completed the MoCA (59% Normal range, 38% Mild CI range, 2% Moderate CI range, and 0.5% Severe CI range). Of the 324, 218 (67%) received BBM: 18.8% had High APS, 67.9% Low APS, and 13.3% Intermediate (e.g. non‐informative) APS. The APS result for participants with a normal MoCA showed 20% with High APS, 12% with an Intermediate APS, and 69% with Low APS. Of those with an impaired MoCA 18% had High APS, 15% Intermediate and 67% low APS. A Fisher’s Exact test determined there was no statistically significant relationship between MoCA impairment and APS category (p‐value 0.68).ConclusionThis study highlights the success of a DTC approach. The MoCA, alone, is insufficient to identify risk of AD in individuals with CI. A more comprehensive clinical evaluation of AD can be enhanced with the addition of a BBM leading to better disease‐modifying strategies.