bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of the combination of tetrahydrocannabinol and melatonin (IGC‐AD1) on blood pressure variability in patients with mild to moderate Alzheimer’s Disease
Authors: Silva‐García David , Gutierrez Evelyn , Sanchez Laura Tatiana , Arbelaez María Juanita , Tangarife Maria Alejandra , Delgado‐Murillo Laura , Rodriguez‐Soacha Diego , Shahnawaz Saadia S , Ghazaryan Varduhi , Naranjo Maria Paula , Venegas Margarita , Pujals Karen Y , De Jesus William Julio , Grimaldi Claudia , Lanctôt Krista L. , Hong L Elliot , Mukunda Ram 
Published: December 2023

AbstractBackgroundBlood pressure (BP) variability (BPV) is a risk factor for Alzheimer’s disease (AD). Medications, such as atypical antipsychotics used to treat neuropsychiatric symptoms (NPS) common in AD, contribute to altering BP. Here we present preliminary data on the use of IGC‐AD1, a combination intervention of tetrahydrocannabinol (THC) and melatonin, on BP and BPV.MethodParticipants with hypertension (n = 12) and mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) were enrolled in a three‐Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, Cohort‐2 and Cohort‐3, one ml QD, BID, and TID of IGC‐AD1 were administered respectively for 14‐days with a minimum of 4‐days washout between Cohorts. For all Cohorts, BP was recorded daily. Coefficients of variation (CV), ∆DBP and ∆SBP (diastolic and systolic blood pressure) were calculated to assess SBP‐variability for each Cohort. A chi‐square was performed to verify whether the difference between controlled and uncontrolled SBP (>140mmHg in more than 20% of values per participant) was related to IGC‐AD1. SBP‐CV difference among Cohorts was determined with a one‐way ANOVA. The difference between active and placebo for each Cohort was assessed with independent t‐tests (dplr R‐Studio). BP‐associated adverse events (AEs) were evaluated daily.ResultVariability measures fell within the normal range (∆DVP = 45.0±13.5 mmHg, ∆SBP = 66.44±22.9 mmHg, CV = 7.6±5.3 mmHg) for all three Cohorts. Cohort‐1 (mmHg): ∆SBP = 42.3±15.56, ∆DVP = 25.6±8.86, CV = 10.14±3.84; Cohort‐2 (mmHg): ∆SBP = 41.9±11.73, ∆DVP = 23±9.7, CV = 8.95±1.96; Cohort‐3 (mmHg): ∆SBP = 39.6±11.76, ∆DVP = 23.6±7.82, CV = 8.84±7.83. IGC‐AD1 had no statistically significant effect between controlled and uncontrolled SBP (X2(2) = 1.15, p = 0.562). There was no SBP‐CV mean‐difference among Cohorts (F (2,27) = 0.589, p = 0.562). No differences were detected between placebo and active (Cohort‐1: t(1.64) = 0.315, p = 0.788, Cohort‐2: t(1.31) = ‐0.225, p = 0.85, Cohort‐3: t(3.53) = 1.63, p = 0.188). While BP related AEs were reported, none were deemed, by the PI, to be associated with IGC‐AD1.ConclusionPreliminary data indicate that IGC‐AD1, a cannabis‐based formulation, in trials to treat NPS did not statistically affect BP or BPV in a MAD study indicating that it may not contribute as a risk factor for AD; warranting a larger placebo‐controlled trial.
A finger prick collection method for detecting blood biomarkers of neurodegeneration – a pilot study (DROP‐AD)
Authors: Huber Hanna , Montoliu‐Gaya Laia , Blennow Kaj , Zetterberg Henrik , Rovira Mercè Boada , Jeromin Andreas , Arús Xavier Morató , Ashton Nicholas J. 
Published: December 2023

AbstractBackgroundPlasma biomarkers have proven to indicate developing cerebral pathologies and injury that underpin neurodegenerative disorders in a non‐invasive manner. However, the measurement of certain blood biomarkers requires on‐site sampling with strict, time‐limited and temperature dependant processing protocols. To further facilitate the usefulness of blood biomarkers, methods for remote and/or unsupervised sample collection would greatly increase the utility as a screening and monitoring tool in secondary care and therapeutic trials.This pilot study investigated a novel method to quantify neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated tau (p‐tau) in capillary dry blood spots (DBScapillary) and venous dry blood spots (DBSvenous).MethodsWe included 77 memory clinic participants from ACE Alzheimer Center Barcelona. DBScapillary, DBSvenous, and EDTA plasma as well as neuropsychological measures were obtained from each participant. A subset (n = 23) had cerebrospinal fluid (CSF) biomarkers. Capillary whole blood was obtained by a macro lancet needle from the left index finger. A total of 65µL of capillary and venous blood were spotted and dried on Noviplex DBS cards, which were shipped overnight without temperature control or cooling to Gothenburg, Sweden. Samples were extracted from DBScapillary and DBSvenous cards, and NfL, GFAP, p‐tau181, and, in a subset (n = 11), p‐tau217 were measured by single molecular array (Simoa). Statistical analysis included Pearson correlation between DBS and EDTA plasma.ResultsDBScapillary GFAP (r = 0.7180, p<0.0001), and NfL (r = 0.6967, p<0.0001) correlated highly with their counterparts in EDTA plasma. We also demonstrated that DBScapillary p‐tau217 (r = 0.8955, p = 0.0002), but not DBScapillary p‐tau181 (r = 0.0132, p = 0.9447) correlated with the same measures in EDTA plasma, likewise DBSvenous GFAP (r = 0.7614, p<0.0001), NfL (r = 0.7701, p<0.0001), p‐tau217 (r = 0.9625, p<0.0001) and p‐tau181 (r = 0.6619, p<0.0001). Moreover, DBScapillary GFAP and DBSvenous GFAP, NfL and p‐tau181 correlated with MMSE, CDR and amyloid status (all p<0.05).ConclusionThis pilot study demonstrates the potential of remote collection and quantification of GFAP, NfL, p‐tau217 and p‐tau181 without low‐temperature storage/transportation or centrifugation (DBSvenous). Our data also suggests that this may be possible from a simple finger prick collection, including p‐tau217. We speculate that this simple, self‐executable method of blood collection would facilitate regular monitoring of patients with suspected neurological conditions.
Sensitivity of individual and composite test scores from the Cogstate Brief Battery to mild cognitive impairment and dementia due to Alzheimer’s disease
Authors: Maruff Paul , Lim Yen Ying , White Josh , Edgar Chris J. 
Published: December 2023

AbstractBackgroundThe Cogstate Brief Battery (CBB) is a computerized cognitive test battery found to detect and confirm cognitive deficits related to Alzheimer’s Disease (AD). As the clinical AD and normative samples used to understand the sensitivity of the CBB to AD have been relatively small and varied in terms of selection criteria, it is important to examine the ability of all CBB measures, and potential composites, to discriminate adults with mild cognitive impairment (MCI) and dementia due to AD from carefully selected cognitively unimpaired (CU) adults.MethodAll speed and accuracy measures from the CBB were examined and both theoretically and statistically derived composites were created, from a sample of 4969 CU adults and 185 adults who met clinical criteria for MCI (clinical dementia rating, CDR = 0.5) or dementia (CDR > 0.5) due to AD.ResultIndividual CBB measures of learning and working memory showed high discriminability for AD‐related cognitive impairment for CDR 0.5 (AUCs ∼ 82‐.85), and CDR > 0.5 (AUCs ∼ .90‐.95). There was also high discrimination ability for theoretically derived CBB composite measures, particularly for the Learning and Working Memory (LWM) composite measure (CDR 0.5 AUC = .83, CDR > 0.5 AUC = .97). Various statistically derived linear composite measures showed discrimination abilities similar to the LWM composite.ConclusionIn older adults, the CBB is an effective instrument for objectively discriminating cognitive impairment due to MCI or AD‐dementia from unimpaired cognition, with the LWM composite being a near‐optimal linear CBB composite for that purpose.
The modifying effects of cardiovascular risk factors on the relationship between lifetime discrimination and cognitive function: Study of Healthy Aging in African Americans (STAR)
Authors: George Kristen M , Gilsanz Paola , Peterson Rachel , Barnes Lisa L. , Glymour M. Maria , Decarli Charles , Whitmer Rachel A. , Mungas Dan M. , Mayeda Elizabeth Rose 
Published: December 2023

AbstractBackgroundDiscrimination is a root cause of health inequities contributing to the excess burden of cognitive impairment among Black Americans. Using the Study of Healthy Aging in African Americans (STAR) we examined whether the effect of lifetime discrimination on late‐life cognitive decline was magnified by early adulthood cardiovascular risk factors.MethodSTAR enrolled long‐term Kaiser Permanente Northern California members ages 50+ who identify as Black/African American. In early adulthood, participants completed Multiphasic Health Check‐ups (MHC; 1964‐1985) where systolic blood pressure (BP), total cholesterol, and body mass index (BMI) were assessed. A latent class analysis identified groups based on responses to the Major Experiences of Discrimination Scale and gender. Standardized z‐scores for executive function (EF) and verbal episodic memory (VEM) were measured over 3 waves (2018‐2022) using the Spanish and English Neuropsychological Assessment Scales. Linear mixed models with random intercepts and slopes associated latent class with cognitive decline adjusting for age at MHC, age at baseline cognitive assessment, education, and assessment mode (in‐person/telephone). Separate models tested class*cardiovascular risk factor interactions.ResultParticipants (n = 646) averaged 27.7(SD = 7.3) years of age at MHC and 68.5(SD = 8.8) at baseline cognitive assessment (Table 1). Four latent classes were identified: men reporting widespread discrimination (Class‐1men; 12%), women reporting widespread discrimination (Class‐2women; 22%), men and women reporting unfair police treatment (Class‐3police; 17%), and men and women reporting little/no discrimination (Class‐4no_discimination; 49%). Using Class‐4no_discimination as reference, those in Class‐2women had significantly higher baseline EF (β(95% CI):0.18(0.03,0.34)) while Class‐1men (β:0.04(‐0.15,0.23)) and Class‐3police (β:‐0.08(‐0.25,0.09)) did not differ (Figure 1). Class‐2women (β:0.17(0.00,0.33)) had higher baseline VEM compared to Class‐4no_discrimination while Class‐1men (β:‐0.40(‐0.60,‐0.19)) and Class‐3police (β:‐0.27(‐0.46,‐0.09)) had significantly lower (Figure 1). There were no differences in rate of decline. There was a systolic BP*class interaction (p = 0.04) where 5 mm Hg higher systolic BP in early adulthood was associated with worse EF for Class‐3police (β:‐0.07(‐0.12,‐0.02)) compared to Class‐4no_discrimination while Class‐1men and Class‐2women did not differ (Figure 2). This pattern was similar for VEM but non‐significant (interaction p = 0.07). We found no interactions with total cholesterol or BMI.ConclusionFor Black Americans, discriminatory experiences may differentially impact late‐life cognition, and elevated systolic BP in early adulthood may exacerbate this harm.
Pneumonia‐induced cerebrovascular dysfunction: potential contributions to dementia
Authors: Chaney Samantha D , McAdams Lauren H , Gwin Meredith S , Bauman Allison J. , Stevens Troy T , Lin Mike , Nelson Amy R. 
Published: December 2023

AbstractBackgroundMany survivors of lung injury, including bacterial pneumonia and COVID‐19, suffer from incident dementia. Patients who have had pneumonia and other infections are at a higher risk for developing Alzheimer’s disease and related dementias (ADRD) (Chu et al., BBI, 2022, Sipila et al., Lancet Infec Dis, 2021, Girard et al., J Gen Intern Med, 2018). There is growing appreciation and strong evidence that neurovascular uncoupling, cerebral blood flow reductions and dysregulation, and breakdown of the blood‐brain barrier (BBB), including the loss of pericytes, are early events in the ADRD pathophysiological cascade. Furthermore, astrocytes and microglia are activated in the ADRD brain and can also disrupt cerebrovascular health and impact cognition. Because these are key events in ADRD, we aimed to determine the effects of bacterial pneumonia on the cerebrovascular system.MethodC57BL/6J mice were intratracheally infected with P. aeruginosa PA103 (ExoU and ExoT competent, 2.5×105 CFU) was introduced as a virulent bacterial strain for 24 or 48 hours. In addition, ΔPcrV (PA103ΔPcrV, 2.5×107 CFU), a mutant lacking a functional Type III secretion system was used for control. Following transcardial perfusion, brains were snap frozen in OCT and serially sectioned. Next, we performed immunofluorescence staining for CD13 (pericytes), lectin (endothelial cells), IgG (BBB leakage), Gfap (reactive astrocytes), and Iba1 (microglia).ResultSignificant BBB leakage of IgG was detected in both cortex and hippocampus 48 hours post‐infection with PA103 compared to ΔPcrV. Significant activation of astrocytes and microglia was detected 48 hours post‐PA103 infection compared to ΔPcrV. Pericyte coverage was unchanged in cortex and hippocampus both 24‐ and 48‐hours post‐infection with PA103 compared to ΔPcrV.ConclusionHere we have shown that bacterial pneumonia causes BBB breakdown and gliosis in young mice. Because BBB breakdown and gliosis are early events in many neurodegenerative diseases leading to cognitive dysfunction, understanding how pneumonia can accelerate these events is extremely timely and important. Future studies should focus on the mechanism(s) by which pneumonia causes cerebrovascular dysfunction and how this may increase ADRD.
Effects of Alzheimer’s disease genetic risk on brain morphometric development in three multiple‐ancestry pediatric datasets
Authors: Vogel Jacob W , Schultz Laura M , Larsen Bart , Seidlitz Jakob , Al‐Sharif Noor B , Barzilay Ran , Cieslak Matthew , Covitz Sydney , Gur Raquel E , Gur Ruben C , Huguet Guillaume , La Joie Renaud , McMillan Corey T , Nilsson Nathalie I.V. , Poline Jean‐Baptiste , Ruparel Kosha , Shinohara Russell T. , Wisse Laura EM , Wolf Daniel , Wolk David A. , Alexander‐Bloch Aaron , Almasy Laura , Satterthwaite Theodore 
Published: December 2023

AbstractBackgroundFew prior studies have investigated whether genetic risk for Alzheimer’s disease (AD) can manifest through altered neurodevelopment of AD‐vulnerable brain regions. This pre‐registered study tests the effects of AD polygenic risk on morphometric neurodevelopment across 3 large datasets totaling 8,364 youths aged 3‐22 (Table 1)MethodPolygenic risk score (PRS) was calculated using PRS‐CS software, with summary scores from Kunkle et al. (2021) for African ancestry individuals (AA) and Jansen et al. (2019) for European ancestry individuals (EA). For EA only, PRS were calculated with (PRS‐APOE+) and without (PRS‐APOE‐) the APOE locus included. All individuals had T1‐weighted MRI processed with FreeSurfer that passed quality assessment checks. ComBAT was used to harmonize sites within‐cohort. Primary analyses investigated effects of PRS, age and their interaction on bilateral hippocampal volume and AD MetaROI cortical thickness using generalized additive models. Age interactions were not evaluated in ABCD due to limited age range. Exploratory analysis examined effects of age and PRS on cortical thickness, volume, surface area and subcortical volume across Desikan‐Killiany regions, adjusting for multiple comparisons (FDR). For exploratory analyses only, ABCD was split into training and test sets. All analyses were conducted for EA and AA separately; sex, total intracranial volume, image quality (Euler number) and ten genetic principal components were included as model covariates.ResultTable 1 summarizes primary results. Hippocampal volume increased with age in 3/6 datasets, while MetaROI thickness decreased with age in all datasets. Surprisingly, increased PRS was associated with larger hippocampi in three datasets. In one dataset only, greater PRS was associated with increased metaROI thickness (Fig 1). 2/3 AA datasets showed age*PRS interactions on hippocampal volume, but in opposite directions. An age*PRS interaction on metaROI thickness was found in one dataset (Fig. 2A‐C). For exploratory analyses, no regions survived multiple comparisons for any contrast in 5/6 datasets; APOE only PRS was associated with larger supramarginal surface area in one dataset (Fig 2E). Effects were not correlated across studies (Fig 2D)ConclusionThis large, pre‐registered study provides little evidence that AD genetic risk manifests during pediatric brain morphometric development.
Targeted plasma eQTL and pQTL to identify potential novel biomarkers for Alzheimer’s Disease in African Americans
Authors: Reddy Joseph S. , Badillo Vanessa M. Colon , Jin Jianli , Lincoln Sarah J. , Ho Charlotte C.G. , Crook Julia E. , Wang Xue , Malphrus Kimberly G. , Nguyen Thuy , Polanco Jean M Marrero , Tamvaka Nicole , Lucas John A. , Graff‐Radford Neill R , Ertekin‐Taner Nilufer , Carrasquillo Minerva M. 
Published: December 2023

AbstractBackgroundGiven the overlap of symptoms between Alzheimer’s disease (AD) and other dementias, it is essential to develop widely accessible biomarkers that will ensure an accurate diagnosis of AD to enable its proper treatment. African Americans (AA) are twice more likely to develop AD than non‐Hispanic whites (NHW) and yet they remain underrepresented in AD research. The few studies conducted in AA suggest that there are different factors that influence AD in this population; therefore, it is possible that different biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study we are testing the hypothesis that genetic variants that show association with AD‐risk in AA and with plasma levels of transcript and proteins may serve as AD biomarkers which are more accessible and less costly than cerebrospinal fluid or neuroimaging biomarkers.MethodsIn 189 AD cases and 183 cognitively unimpaired (CU) AA participants of the Florida Consortium of African American Alzheimer’s Disease Studies (FCA3DS), we performed targeted DNA sequencing of 10 AD‐associated loci. Genetic variants were tested for association with plasma transcripts and plasma total tau protein levels previously measured in this cohort using a nanoString® custom panel (Reddy J, et al. 2022) and Simoa assays (Deniz K, et al. 2021), respectively. In receiver operating characteristic (ROC) analyses, the most significant expression/protein quantitative trait loci (eQTL/pQTL) were added sequentially to a base model that included only age and sex to identify eQTL/pQTL that improved the accuracy to correctly classify AD cases vs. CU.ResultsOf the 5112 variants identified in the targeted sequencing, 71 were nominally associated (p<0.05) with plasma transcript/protein levels and with AD‐risk. ROC analysis of age, sex, eQTL/pQTL in APOE, ABCA7, AKAP9, EPHA1, SORL1, and TLR4, and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE‐ɛ4 dosage achieved 77.6% area under the curve (AUC) to discriminate AD vs. CU, a 19.9% improvement over a model that only included age and sex.ConclusionsPlasma transcript levels and eQTL/pQTL are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.
Quantifying associations of four major proteinopathies with grey matter atrophy: an imaging‐pathology study
Authors: Phillips Jeffrey S , Robinson John L. , Cousins Katheryn A Q , Das Sandhitsu R. , Yushkevich Paul A. , Wolk David A. , Lee Eddie B , McMillan Corey T , Trojanowski John Q , Grossman Murray , Irwin David J. 
Published: December 2023

AbstractBackgroundGross atrophy observed on MRI provides a clinically useful marker of possible neurodegenerative disease. However, autopsy studies of polypathology suggest atrophy is likely driven not by a single proteinopathy but also co‐pathologies. We hypothesized that in a clinically heterogeneous autopsy sample, amyloid‐β, tau, α‐synuclein, and TDP‐43, would co‐occur within regions, and that co‐pathologies would have independent associations with grey matter atrophy.MethodT1‐weighted antemortem MRI was available in 121 patients with postmortem ordinal pathology ratings (0 = none; 1 = mild; 2 = intermediate; 3 = severe). Primary neuropathologic diagnoses included Alzheimer’s disease (AD; n = 52), amyotrophic lateral sclerosis (n = 2), frontotemporal lobar degeneration due to tau (n = 29) and TDP‐43 (n = 22), and Lewy body disease (16). Regional volumes were expressed as W‐scores adjusting for age, sex, and intracranial volume for 10 regions spanning the limbic system, neocortex, and subcortex. We used mixed effects models with a random intercept per patient to regress W‐scores on ordinal pathology ratings.ResultAmyloid‐β and tau co‐occurred in all regions, reflecting the prevalence of AD neuropathologic change (Fig. 2, top). Alpha‐synuclein and TDP‐43 pathology were highest in amygdala, anterior cingulate, entorhinal cortex, and hippocampus, where they frequently co‐occurred with amyloid‐β and tau. Neocortical regions including middle frontal, angular, and superior/middle temporal cortex had intermediate rates of co‐pathology, while thalamus, striatum, and globus pallidus had the lowest polypathologic burden (Fig. 2, bottom). Ordinal measures of tau [F(3,1073) = 24.1, p<0.001], TDP‐43 [F(3,1073) = 13.7, p<0.001], and ‐synuclein [F(3,1073) = 4.3, p<0.005] burden were inversely associated with regional volumes, but amyloid‐ [F(3,1073) = 1.8, p>0.15] was not. An increase in ordinal tau scoring by one unit was associated with a mean reduction of ‐0.29 in regional W‐score; for TDP‐43, a decrease of ‐0.51; and for α‐synuclein, a decrease of ‐0.16.ConclusionMixed proteinopathies were common at the regional level in limbic and neocortical structures. Using blinded ordinal pathology scoring, TDP‐43 was associated with greater atrophy than tau; α‐synuclein had a smaller but significant association. Amyloid‐β was not associated with atrophy when adjusting for tau. Results suggest co‐pathologies have a measurable effect on observed brain atrophy.