bluuebunny/crossref_metadata_2025_split huggingface dataset:
Consequences of Pathogenic Tau Expression in Mouse Locus Coeruleus
Authors: Korukonda Anuradha , Marriott Alexia , Weinshenker David 
Published: December 2023

AbstractBackgroundDuring the early stages of Alzheimer’s disease (AD), patients often suffer from prodromal symptoms such as anxiety, impulsivity, depression, agitation, and sleep disturbances prior to the onset of cognitive impairment. Incidentally, the brainstem noradrenergic locus coeruleus (LC) is the first structure to develop hyperphosphorylated ‘pretangle’ tau pathology in the human brain. Furthermore, norepinephrine (NE) influences several physiological processes such as sleep/wake cycle, arousal, stress, mood, and attention which have been implicated in the prodromal behavioral abnormalities. While clinical studies show significant correlations between LC dysfunction and neuropsychiatric symptoms, a causal relationship between early tau accumulation in the LC and the manifestations of prodromal behaviors remains to be resolved. To explore this, we developed a translationally‐relevant tau mouse model that recapitulates the ‘LC first’ phenomena commonly observed in humans.MethodAdult male and female tyrosine hydroxylase (TH)‐Cre mice aged 4 months underwent intra‐LC infusions with a Cre‐dependent adeno‐associated virus (AAV) expressing mCherry, wild‐type (WT) human tau or P301S mutant human tau (n = 3/group). 3 months post‐infusion, mice underwent a panel of behavioral tests to assess sleep latency, locomotor activity, compulsivity, stress‐induced anxiety‐like behavior, association memory deficits, impulsivity, and attentional impairments. Following behavioral tests, brain sections comprising the LC, hippocampus and prefrontal cortex (PFC) were immunostained with TH to assess for LC integrity, AT8 to detect pretangle tau, NE transporter (NET) to evaluate NE fiber intensity in projection regions, and GFAP and IBA1 to identify neuroinflammatory markers. Immunoreactivity (IR) will be calculated as a measure of fluorescence via ImageJ.ResultIt has been proposed that tau accumulation in the LC may provoke mild to moderate damage in LC neurons, triggering compensatory mechanisms such as LC hyperactivity. It is hypothesized that at 3 months, LC‐specific tau pathology will result in hyperarousal, compulsivity, anxiety‐like behavior, and impulsivity. In tandem, human tau‐expressing mice are expected to display increased TH, reflecting LC hyperactivity, neuroinflammatory markers and reductions in NE fibers in LC‐projecting regions. These findings will be presented in July 2023.ConclusionThis research will elucidate the role of LC in governing prodromal symptoms. Further studies will be needed to assess molecular mechanisms underlying tau‐mediated LC dysfunction in early AD.
Thalamic Contributions to Functional Circuitry in Preclinical Alzheimer’s Disease
Authors: Li Joyce S , Tun Samantha M , Lacadie Cheryl , Fredricks Carolyn 
Published: December 2023

AbstractBackgroundThalamic nuclei are heterogeneously impacted by Alzheimer’s disease (AD) pathology. The anterior thalamus shows tau deposition early on in AD, while other nuclei, such as the mediodorsal (MD) thalamus are spared by tau until much later in the disease process (Braak and Braak, 1991). Furthermore, anterior and MD thalamus have dissociable roles in memory performance – the anterior has a greater role in recollective memory, while the MD plays a role in familiarity. Additionally, the anterior thalamus has direct anatomical links to brain regions implicated in poor short‐term memory performance in AD, while MD thalamus connectivity is primarily to regions spared of AD pathology until late. We sought to identify differences in functional connectivity between the anterior and MD thalamus in amyloid negative and positive individuals.MethodWe examined resting‐state functional MRI data from the A4 study (n = 569), including 254 healthy controls and 315 individuals with preclinical AD based on amyloid SUVR>1.14 (Table 1). We assessed functional connectivity of anterior and MD thalamus to the whole brain using 2mm radius spherical seeds at the center of mass of Morel atlas nuclei. All results were covaried for age, sex, handedness, and years of education.ResultsAnterior thalamic activity was positively correlated with parahippocampal gyrus, fusiform, and insula, and negatively with the striatum and thalamus. MD thalamic activity was positively correlated with the amygdala, ventral striatum, and anterior cingulate, and negatively correlated to the superior temporal gyrus and regions of the parieto‐occipital lobe. In preclinical AD, compared with HCs, the positive correlations in either thalamic nuclei were lost.ConclusionThe thalamic functional connectivity observed agrees with preexisting literature dissociating structures related to the anterior and MD thalamus. Our results provide a basis for further exploration of thalamic nuclei to AD‐involved functional networks, as well as future analysis of the observed connectivity measures to cognition.
Association of individual and multiple comorbid neuropathologies with cognitive decline in the oldest‐old: Results from The 90+ Study
Authors: Biswas Roshni , Jiang Luohua , Kawas Claudia H. , Sajjadi S. Ahmad , Montine Thomas J. , Bukhari Syed A. , Corrada María M. M. 
Published: December 2023

AbstractBackgroundAge‐related neuropathologies are common in the oldest‐old and associated with cognitive decline. In this study, we examined the associations of individual and multiple comorbid neuropathologies with cognitive decline in participants who had normal cognition in at least one in‐person visit during their time in The 90+ Study.MethodOur study included 251 individuals from The 90+ Study‐ a longitudinal study on aging, who had at least 2 in‐person visits, had normal cognition in at least one of them and had autopsy data. We used longitudinal Mini Mental State Examination (MMSE) scores to assess cognitive trajectories. For the first part of our analysis, we examined individual neuropathologies that were evaluated as: Alzheimer’s Disease neuropathologic change (ADNC) (intermediate/high), presence of Cerebral amyloid angiopathy (CAA), Microinfarcts (2+), atherosclerosis, arteriolosclerosis, Lewy body disease (LBD), Hippocampal sclerosis (HS), Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), and Age‐related tau astrogliopathy (ARTAG). For the second part of our analysis, we examined multiple comorbid neuropathologies. For this analysis we recoded each neuropathology as: 0 for absent/negligible levels, 0.4 for intermediate, or 1 for severe. These recoded scores were added to create four summary indices: all pathology index (total of all individual neuropathologies), vascular index (CAA, Microinfarcts, atherosclerosis, and arteriolosclerosis), neurodegenerative index (ADNC, LB, HS, and LATE‐NC) and non‐AD neurodegenerative index (LB, HS, and LATE‐NC). We used linear mixed effects models to examine the associations of individual neuropathologies and the pathology indices with cognitive decline.ResultAt baseline, participants had a mean age of 93 years and a mean MMSE score of 27.6. Mean follow up time was 5.1 years (Table1). Presence of LBD (ß = ‐0.20; p = 0.07), and HS (ß = ‐0.24; p = 0.06) trends toward to an association with faster cognitive decline (Table2). All pathology index (ß = ‐0.10; p = 0.01), neurodegenerative index (ß = ‐0.17; p = 0.003) and non‐AD neurodegenerative index (ß = ‐0.16; p = 0.02) were significantly associated with faster cognitive decline (Table3).ConclusionIn individuals who maintain normal cognition until age 90+ and then start declining, the rate of cognitive decline is related to the burden of neuropathologies, particularly neurodegenerative neuropathologies. Therefore, multiple comorbid neuropathologies need to be targeted for preventing cognitive decline in the oldest‐old.
Validation of the Ten‐word Test for Immediate Memory in Middle‐Aged and Older Population with Subjective Cognitive Decline and Mild Cognitive Impairment
Authors: Wang Ziqi , Xu Lisi , Wang Yu , Li Hongyi 
Published: December 2023

AbstractBackgroundTo validate the ten‐word test for immediate memory from the Alzheimer’s Disease Assessment Scale‐Cognitive section (ADAS‐Cog) in detecting subjective cognitive decline (SCD) and mild cognitive impairment (MCI).Method79 people aged 38∼80 years old participated in the study and they were classified as SCD (n = 55) or MCI (n = 24).ResultThe the Mann‐Whitney U test showed that the ten‐word test score was significantly different in SCD compared to MCI (p = 0.001, Figure 1). In particular, a cut‐off score of 4.15 points had an 63% sensitivity and 87% specificity for discriminating MCI from SCD (AUC = 0.73, p = 0.001), while a cut‐off score of 4.15 also had a sensitivity of 79% and a specificity of 83% for discriminating MCI from SCD in age > 60 years old adults (AUC = 0.82, p = 0.001), and a cut‐off score of 4.35 points had a sensitivity of 90% and a specificity of 95% for discriminating MCI from SCD in those age > 60 years old adults with education level > 9 years (AUC = 0.93, p < 0.001) (Figure 2‐3). Convergent validity was found between the ten‐word test and ADAS‐cog total scores (r = 0.56, p < 0.001), and the Mini‐Mental State Examination (MMSE) (r = ‐0.28, p = 0.013) and the Montreal Cognitive Assessment‐Basic (MOCA‐B) (r = –0.20, p = 0.078).ConclusionThe ten‐word test for immediate memory from the ADAS‐Cog is a good to fair screening tool with adequate discriminant validity for administration in people with SCD and MCI.
AD Biomarkers in Chronic Kidney Disease and Kidney Transplant
Authors: Gupta Aditi , Morris Jill K , Kueck Paul J. , Blankenship Anneka , Mahnken Jonathan D , Young Kate 
Published: December 2023

AbstractBackgroundBlood biomarkers of Alzheimer’s disease (AD) are elevated in chronic kidney disease (CKD). Whether this is due to deceased kidney clearance or increased production, and how they change with kidney transplant (KT), is unclear.MethodWe examined serum AD biomarkers from CKD patients pre‐ to post‐KT and compared findings with controls without CKD or AD. Analyses were performed on a Simoa HD‐X, using pTau181 and Neuro 4 Plex E assays.Age was used for covariate adjustment in linear mixed models (LMM) analyzing phosphorylated tau 181 (ptau181), neurofilament light (NfL), amyloid beta (AB42, AB40, 42/40), and glial fibrillary acidic protein (GFAP). Change in p‐tau181 was our primary outcome. LMM included age and levels for control, pre‐KT, or 12‐weeks or 1‐year post‐KT. Based on residual patterns, the natural log (In) of each measure was used for final analyses. Linear contrasts were used to generate estimated differences between group/time points from age‐adjusted models. These included averaged pre‐KT, post‐KT, and control comparisons. Two degree‐of‐freedom tests compared the post‐KT measures to pre‐KT and controls.ResultThe 59 CKD patients were 52±12 years old and 13 controls were 51±8 years old. Pre‐KT, ln(p‐tau181) was higher than controls (p<0.0001) and post‐KT (p<0.0001) (Figure). Post‐KT p‐tau181 greatly decreased but remained higher than controls (p = 0.0004). There was no difference between 12 weeks and 1 year post‐KT levels (p = 0.70). ln(pTau) increased with age (p = 0.06). ln(NfL) followed a similar pattern; pre‐KT levels were higher than controls (p<0.0001) and post‐KT (p<0.0001). Post‐KT levels decreased but remained higher than controls (p<0.0001). 12‐week and 1‐year post‐KT levels did not differ (p = 0.57). Levels increased with age (p<0.0001). Pre‐KT AB42 was higher than controls (p<0.0001) and post‐KT (p<0.0001). Post‐KT, levels decreased but remained higher than controls (p = 0.005) and continued declining 1‐year post‐transplant (p = 0.01). In(AB40) and In(GFAP) showed the same pattern. The AB42/AB40 was not different pre‐KT vs controls (p = 0.58) and did not change following KT. Cognitive function improved post‐KT. Patients with residual kidney function had lower baseline levels of AD blood biomarkers.ConclusionIn severe CKD, blood biomarkers of AD are dependent on kidney function and caution should be used in interpreting them.
Association between retinal layer thickness and cerebral white matter hyperintensities in older adults
Authors: Han Ji Won , Kim Hyeong Min , Kwon Min Jeong , Park Jieun , Kim Jun Sung , Woo Se Joon , Kim Ki Woong 
Published: December 2023

AbstractBackgroundThe brain and retina may share pathophysiological mechanisms in various central nervous system disorders, suggesting the potential associations between retinal layer thickness and cerebral white matter hyperintensities (WMH).MethodA total of 149 participants without dementia aged over 65 years (mean age: 75.4, SD: 5.4, range: 65‐91; male: 90 [60.4%]) from the randomly sampled community‐dwelling prospective cohort were included in the analysis. Using spectral‐domain optical coherence tomography, we assessed the thickness of 6 retinal layers in the macular region, the peripapillary retinal nerve fiber layers, and the subfoveal choroid. We classified WMH into 3 groups using the distance from the ventricle surface: juxtaventricular (JVWMH, < 4mm), periventricular (PVWMH, >4mm, <14mm), and deep WMH (DWMH > = 14mm). The associations between retinal layer thickness and WMH volume were examined using linear regression models adjusting age, sex, comorbid hypertension, and diabetes.ResultThe thicknesses of superior outer, inferior outer ganglion cell layers (GCL) and superior outer, inferior outer, total outer inner plexiform layers (IPL) were negatively associated with the total WMH, PVWMH, and DWMH volumes. Reduced thicknesses of total outer GCL and temporal outer inner nuclear layer (INL) were associated with higher total WMH and PVWMH volumes. Center GCL thickness was positively associated with JVWMH volume, and nasal outer GCL thickness was negatively associated with DWMH volume.ConclusionOuter GCL and IPL thicknesses may be associated with WMH volume in older adults. This study may also suggest differential associations based on etiology between retinal layer subfields and WMH subgroups.
Joint Exposure‐Response Analysis of PET Amyloid Plaque Data from the BACE1 Inhibitor Verubecestat and Amyloid mAbs Trials in Prodromal to Moderate Alzheimer’s Disease
Authors: van Maanen Eline , Stone Julie A , Bennacef Idriss , Duffull Stephen , Robey Seth 
Published: December 2023

AbstractBackgroundPositron‐emission tomography (PET) with amyloid radiotracers allows the quantification of pathological amyloid deposition in brain tissues. An exposure‐response (E‐R) analysis of individual study data of the β‐secretase‐1 inhibitor verubecestat and summary level data of four amyloid mAbs in patients with Alzheimer’s disease (AD) was conducted, to quantify the drug effects and plaque turnover rates and facilitate prediction of unstudied regimens.MethodIndividual (n = 188) verubecestat amyloid‐PET plaque data and exposures from APECS [Egan et.al, 2019] were pooled with summary. amyloid‐PET data and serum exposures from literature for aducanumab [Sevigny J, et al. 2016], donanemab [Lowe SL, et al. 2021, Lily ADPD, 2021], gantenerumab [Klein G, et al. 2019, Portron A, et al. 2020] and lecanemab [Swanson CJ, et al. 2021]. Amyloid plaque levels in SUVR units were converted to Centiloid [Klunk WE, et al. 2015]. All data were fit simultaneously in a joint model by nonlinear mixed‐effects modelingResultAn indirect response (turnover) model with verubecestat inhibiting plaque formation, and amyloid mAbs stimulating plaque removal well represented the available data (Figure 1). All plaque time course data from natural progression (control arms), β‐secretase‐1 inhibition and amyloid mAb treatment arms were well described by a joint model. The plaque turnover was estimated to be 0.00028 per day, corresponding to a half‐life of plaque of ∼ 6.8 years. Verubecestat AUC50 was estimated as 0.313 uM*h, commensurate to a 93.5% reduction in plaque formation at the typical 40 mg exposure and consistent with the >60% reductions in CSF Aβ40 and 42 observed in APECS. Aducanumab 10 mpk Q4W, donanemab 1400 mg Q4W, lencanemab 10 mpk Q2W, and gantenerumab 1200 mg SC Q4W were estimated to results in 13.5‐, 16.4‐, 16.6‐, and 12.6‐fold increases in plaque removal rate, respectively.ConclusionThe joint turnover model, linking drug exposure with amyloid plaque load, was adequate to describe natural progression and treatment response, and allows for estimation of the underlying turnover rate. This approach improves cross‐study comparisons and prediction of alternative regimens and therapeutic approaches by accounting for differences in baseline plaque load, dosing and titration regimens, and mechanism of action.
Baseline cognitive dispersion is related to increases in white matter hyperintensities in cognitively preserved older individuals
Authors: Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Solé‐Padullés Cristina , Cabello‐Toscano María , Abellaneda‐Pérez Kilian , Perellón‐Alfonso Ruben , Perera‐Cruz Oriol , Bargalló Núria , Bartrés‐Faz David 
Published: December 2023

AbstractBackgroundCognitive dispersion (CD), understood as intra‐individual variability in performance, is considered a sensitive marker of prodromal stages of Alzheimer’s Disease (AD; Halliday et al. J. Intell 2018;6(1):12), and it is thought to complement cognitive performance (CP) in predicting age‐related changes (Costa et al. ClinicNeuropsychol 2019;33(2)). Moreover, white matter hyperintensities (WMH) are a common age‐associated finding that especially impacts processing speed (Boutzoukas et al. Front in AgingNeurosci 2021;13) and executive function (Papp et al. NeuropsycholDev 2014;21(2)). Therefore, we aimed to investigate (i) associations between CD, CP, and WMH, and (ii) whether WMH age‐related changes can be better predicted by baseline CD or CP in a cognitively normal aging sample.MethodOne hundred and three healthy elders (age: 68.61±3.01 years; 72 females) underwent a neuropsychological assessment and a magnetic resonance image acquisition and repeated them after 2 years. Based on processing speed and executive function scores, we computed a baseline CD (i.e., CD‐tp1; using the intraindividual standard deviation method, Costa et al. Clinic Neuropsychol 2019;33(2)) and a CP (calculated with principal component analysis) at both time‐points (i.e., CP‐tp1, CP‐tp2). 3D‐FLAIR sequence was used to estimate WMH volumes (i.e., WMH‐tp1, WMH‐tp2) using the SPM12 Lesion Segmentation Toolbox (Schmidt et al. Neuroimage 2012;59(4)). The baseline volumes were subtracted from the follow‐up ones to obtain the difference (i.e., CP‐diff, WMH‐diff). Statistical analyses were linear regressions adjusted by age, sex, years of education, and intracranial volume for WMH analyses. Paired t‐tests were used for the longitudinal approach.ResultThere was a negative cross‐sectional relationship between CD‐tp1 and CP‐tp1 (B = ‐.240, t = ‐3.034, p = .004; Fig1), while those cognitive measures were unrelated to WMH‐tp1 volumes. Longitudinally, we detected a significant increase in WMH (t = 7.244, p<.001), while CP remained stable and there were no significant associations between CP‐diff and WMH‐diff. The main finding was the significant relationship found between WMH volume increases (i.e., WMH‐diff) and CD‐tp1 (B = ‐.320, t = ‐3.060, p = .003; Fig2), but not with CP‐tp1.ConclusionThe results show that in healthy elderly individuals who evidenced cognitive stability in processing speed and executive function, the CD is a sensitive marker to predict significant age‐related increases in WMH, which would be beneficial in the AD‐continuum.
Dementia Risk Estimation: Individual Needs and Preferences– Preliminary Data of the PreTAD‐Study
Authors: Gerards Michelle , Baumeister Annika , Hübner Constanze , Ribaldi Federica , Marquié Marta , Cantero‐Fortiz Yahveth , Schmitz‐Luhn Björn , Wittrock Julia , Schwegler Carolin , Boada Mercè , Frisoni Giovanni B , Woopen Christiane , Jessen Frank , Rostamzadeh Ayda 
Published: December 2023

AbstractBackgroundDue to new, more reliable and accessible technologies, a paradigm shift from curative to predictive and preventive medicine is emerging. Despite progress in the field of Alzheimer’s dementia risk estimation, little is known about the individual perspectives in this regard. The tri‐national PreTAD (The Predictive Turn in Alzheimer’s Disease: Ethical, Clinical, Linguistic and Legal Aspects) project aims to study the perspectives of individuals from the general population, first‐degree relatives of persons with Alzheimer’s dementia, APOE4 allele carriers, and of individuals with subjective cognitive decline (SCD) on individual risk factor assessment and dementia risk estimation. In a quantitative and qualitative longitudinal study, needs, preferences and decision‐making parameters will be conducted.MethodFor the quantitative study, hypothetical scenarios on predictive AD diagnosis for an individual person were developed. Based on these scenarios, instruments to measure psychological distress, subjective well‐being, quality of life, willingness to make lifestyle changes, and to take preventive measures were applied. The qualitative approach uses individual interviews to obtain complementary in‐depth information on personal preferences. Results of the pilot study with 10 cognitively unimpaired healthy participants and 10 participants with SCD are reported.ResultThe participants of the pilot study wanted to know their estimated personal risk of developing Alzheimer’s dementia. Higher test accuracy was more important than low invasiveness. In the pilot data, age and the possibility of influencing the risk by lifestyle changes, but also the attitude of relatives, influenced the decision for risk estimation. Willingness to assess dementia risk seems to be independent of the absence of causal treatment options.ConclusionThe PreTAD project will provide a deeper comprehension of needs and preferences regarding the individual dementia risk estimation. From an individual point of view, there seems to be an interest in risk assessment and prediction, which is influenced by a variety of factors. The findings of the PreTAD project will help to incorporate the perspectives of potential users risk estimation in the development of guidance for counseling and clinical management in predictive and preventive approaches in the field of dementia.