bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular primary cilia in the pathogenesis of hypertension and Alzheimer's Disease
Authors: Forero Kathleen , Messer William S , Aboualaiwi Wissam 
Published: December 2022

AbstractBackgroundPrimary cilia are microtubule‐based organelles, extending from the surface of cells to sense extracellular signaling cues. We demonstrated that the inability of endothelial cilia to sense and transmit fluid‐shear stress can lead to nitric oxide (NO) deficiency and cause vascular HTN. HTN can cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment, contributing to the progression of AD. It is well documented that decreased biosynthesis of NO contributes to cerebral amyloid angiopathy in AD patients through increased deposition of Aβ. Disruption of the cholinergic neurotransmitter pathway, which is important for cognition, memory and learning abilities has been reported in AD patients. However, the connection between cilia and mAChR signaling in the brain has never been investigated. We propose a bold idea to look at the pathophysiological roles of cerebrovascular ciliary receptors in BP and AD.MethodImmunofluorescence of human brain endothelial cells (HBECs) were employed to study AChM3R localization and its downstream effectors. Cilia length and function (eNOS activation) studies were carried out to examine if mAChRs activation would enhance cilia structure and function. siRNA‐mediated knockdown of Tulp‐3 was performed to block AChM3R trafficking to primary cilia and study its activity. HBECs were exposed to synthetic Aβ to study their effect on cilia structure and ciliogenesis. Vascular‐specific cilia and AChM3R knockout mice were generated to study blood pressure and AD manifestations.ResultWe discovered that AChM3R, PIP2, and eNOS localize to primary cilia. mAChR‐specific activation (CDD‐0102A) increases cilia length in HBECs and cilia formation in cilialess Tg737 cells and was also associated with an increase in eNOS activity. Exposure to 2.5 μM human Aβ42 resulted in significant reduction in primary cilia length and ciliation percentage. RNAi‐mediated knockdown of Tulp3 caused a significant decrease in AChM3R trafficking to the cilia, associated with altered activity, suggesting that ciliary AChM3R localization is important for its activity. Vascular‐specific AChM3R and Tg737 KO mice developed high BP. Studies to examine cognitive function in our animal models are underway.ConclusionPrimary cilia play an important sensory role by hosting proteins and signaling molecules important for the regulation of blood pressure and cognitive function.
Integrative single‐nucleus RNAseq analysis identifies cell‐type‐specific expression perturbations in progressive supranuclear palsy
Authors: Min Yuhao , Wang Xue , İş Özkan , Patel Tulsi , Reddy Joseph S. , Nguyen Thuy , Chalk Jessica L , Tutor‐New Frederick Q , Crook Julia E. , Carrasquillo Minerva M. , Dickson Dennis W. , Zhang Ke , Allen Mariet , Ertekin‐Taner Nilufer 
Published: December 2022

AbstractBackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by cell‐type‐specific tau lesions in neurons and glia. Using bulk brain RNAseq, we previously identified PSP‐associated genes and co‐expression networks that are enriched with cell‐type marker genes. We extended our work to identify cell‐type‐specific expression perturbations in PSP using a systems approach and in vivo validations in a model system.MethodSingle‐nucleus RNAseq (snRNAseq) was performed using 33 frozen brain temporal cortex (TCX) samples from PSP and control brains. After quality control (QC), integration, and clustering of nuclei, each cluster was annotated for its cell type. We identified differentially expressed genes (DEG) in PSP and further investigated them using an independent bulk RNAseq dataset comprising 408 PSP and control TCX samples for replication and assessing co‐expression patterns. Top DEGs were identified and then validated using external bulk RNAseq datasets from a tau transgenic mouse model. Further, the ability of the validated DEGs to rescue tau‐mediated cellular toxicity was evaluated in a tau transgenic Drosophila model.ResultAfter QC, 30 clusters comprised of 27,284 nuclei were obtained, encompassing two neuronal and six glial cell types. DEGs of each cluster revealed cell‐type‐specific PSP associations. Notably, many of the up‐regulated DEGs in the astroglial clusters were members of the bulk RNAseq co‐expression modules that were also up‐regulated in PSP and enriched with astrocytic markers. There were also consistent findings for the up‐regulated DEGs in the endothelial and microglial clusters, and for down‐regulated DEGs in the oligodendroglial clusters. Subsequently, we prioritized 240 DEGs with congruent cell‐type‐specific perturbations in snRNAseq and bulk RNAseq and validated 29 of those using transgenic mouse model data. Lastly, a significant number of the up‐regulated glial genes, when knocked down in a tau transgenic Drosophila model, led to reduced tau‐mediated cellular toxicity, suggesting novel potential therapeutic avenues.ConclusionPSP brains demonstrated robust cell‐type‐specific gene expression perturbations in the glial cells populations that were validated across different datasets. Importantly, inhibiting the up‐regulated expression perturbations rescued tau‐mediated toxicity in a Drosophila model. Our findings highlight the cell‐type‐specific transcriptome changes in PSP and provide potential therapeutic options for primary tauopathies.
Absence of Apolipoprotein E Exacerbates Prion Pathology and Promote Microglial Mediated Neurodegeneration
Authors: Lizińczyk Anita M , Pankiewicz Joanna E. , Franco Leor A. , Diaz Jenny R , Ariza Mitchell Marta , Sadowski Martin J. 
Published: December 2022

AbstractBackgroundBoth Alzheimer’s disease and prionoses are neurogenerative disorders, which involve misfolded protein deposition and transition of homeostatic microglia to their neurodegenerative phenotype. In prionoses, accumulation of toxic PrPSc protein constitutes the culprit of pathogenesis. Neurodegenerative phenotype microglia (MGnD) appear early in the course of disease and play opposing roles in PrPSc mediated neurodegeneration. Whilst clearance of PrPSc has a disease‐limiting effect, MGnD‐driven neuroinflammation is deleterious to neurons. Apolipoprotein (apo) E is a pleiotropic protein, which controls MGnD phagocytic and inflammatory characteristics. Despite prominent role of microglia in prionoses, involvement of apoE in their pathogenesis has not been established.MethodWild type (WT) and Apoe‐/‐
mice, both on the B6 background, were inoculated with 22L mouse adapted scrapie strain or normal brain homogenate. Neuropathological and biochemical analyses were performed 15 and 23 weeks post inoculation (WPI) on asymptomatic and overly symptomatic animals, respectively. NanoStringTM analysis of microglia and astrocytic transcriptomic markers was performed at 23WPI.ResultPrion infection of WT mice upregulates total brain apoE level and effects cell‐type shift in the apoE expression, downregulating astrocytic apoE while increasing microglial apoE 24‐folds. 22L
Apoe‐/‐
mice have significantly shorter disease incubation period, higher load of spongiform changes, and increased total brain PrP and PrPSc levels compared to 22LWT mice. In 22L
Apoe
‐/‐ mice astro and micro gliosis appears earlier and is more robust compared to 22LWT mice. Transcriptomic analysis shows significantly higher level of PAN and A1, but not A2 astrocytic markers and MGnD markers in 22L
Apoe
‐/‐ mice compared to 22LWT animals. Microglia in 22L
Apoe
‐/‐ mice feature impaired neuronal phagocytosis and produce increased level of pro‐inflammatory interleukins and cytokines. 22L
Apoe
‐/‐ mice show higher neuronal loss and greater tempo of neuronal degeneration than 22LWT mice.ConclusionOur results indicate the net effect of apoE in prion pathogenesis is protective. ApoE facilitates clearance of PrPSc and dying neurons by microglia, which becomes ineffective in the absence of apoE. Remnants of disintegrating neurons promote MGnD phenotype transition and inflammatory cascade propagating the vicious cycle of neuronal death and neuroinflammation. Our data also indicate homeostatic microglia transit to the MGnD even if they do not express apoE.
Patient and Care Partner Ratings of Communication Participation in Frontotemporal Dementia
Authors: Utianski Rene L , Clark Heather M , Martin Peter R , Stierwalt Julie A.G. , Duffy Joseph R , Botha Hugo , Ali Farwa , Josephs Keith A 
Published: December 2022

AbstractPrior studies have shown communication‐related participation restrictions in patients with degenerative disease do not always match clinician judgment of symptom severity. Relatedly, there is a growing body of literature documenting discrepancies between patients with dementia and care partner perception of participation restrictions. However, it is not known how care partner perceptions of communication participation restrictions match or diverge from the patient's experience, which was the topic of this study.Toward that end, 28 patients with apraxia of speech and/or dysarthria associated with primary progressive apraxia of speech, nonfluent/agrammatic primary progressive aphasia, or progressive supranuclear palsy, all types of frontotemporal dementia, were seen for speech‐language examinations. The patients and their care partners were asked to independently complete the Communication Participation Item Bank (CPIB), short form, which is a 10‐question survey about communication in different contexts; higher scores reflect less interference from their condition on communication. Care partners were instructed to complete the form with their perception of the patient's restrictions. The total CPIB score (maximum 30) and difference scores were calculated and visualized.The data (Figure) suggest mismatches exist in care partner and patient ratings of communication participation restrictions. Of 28 patients, only 1 pair had identical scores, each rating severe interference in all communication contexts. 57% of patients rated communication as less impacted (higher scores) compared to their family member, leaving 39% of family members rating communication as less impacted than their loved one's perception. This study lays the foundation for future research to include patient and care partner ratings when examining the benefit of impairment‐based therapy, utilization of compensatory speech strategies, effectiveness of such strategies, and impact of other augmentative or alternative means of communication. The CPIB may be useful to document reduced psychosocial impact of disease and diminished burden and burnout on care partners with different intervention options. Future studies will explore possible differences between FTD phenotypes and, more specifically, whether 1) the motor speech disorder (MSD) disorder is primary or secondary to other motor impairment, 2) the nature or severity of the MSD, or 3) concomitant cognitive‐communication impairment predict the existence of and/or direction of a discrepancy.
Cerebrovascular reactivity is related to enlarged perivascular spaces in the basal ganglia among cognitively normal older adults
Authors: Libecap Timothy Justin , Bauer Christopher E. , Zachariou Valentinos , Raslau Flavius D , Gold Brian T. 
Published: December 2022

AbstractBackgroundCerebral small vessel disease (cSVD) is characterized by several in‐vivo neuroimaging biomarkers including enlarged perivascular spaces (ePVS). PVS are fluid‐filled spaces that play a role in the glymphatic system’s removal of brain waste. Arterial pulsatility drives waste removal through the PVS. Thus, arterial stiffness, a common feature of brain aging, may lead to waste accumulation and perivascular space enlargement.MethodWe explored the relationship between arterial stiffness and ePVS counts in 80 cognitively normal older adults ranging in age from 60‐85. Participants were scanned on a 3T Siemens Prisma scanner with a 64‐channel head coil. Arterial stiffness was assessed using cerebrovascular reactivity (CVR), a measure of the ability of cerebrovasculature to dilate in response to hypoxia. Blood‐oxygen‐level‐dependent contrast imaging (BOLD) functional magnetic resonance imaging (fMRI) was used in conjunction with blocked administration of hypercapnic gas. CVR was computed in specific regions by dividing change in BOLD signal by change in end‐tidal CO2. All ePVS counts were performed on T1 MPRAGE and T2 FLAIR images while blinded to participant demographics and under the direction of a neuroradiologist. ePVS were defined as regions of hypointensity less than 3mm in diameter on T1 imaging and were distinguished from mimics by absence of T2 FLAIR hyperintensity. ePVS were individually and manually counted in a single, representative slice in the axial plane of the basal ganglia (BGePVS), centrum semiovale, hippocampus, and midbrain.ResultRegression analyses controlling for age, sex, intracranial volume, and education demonstrated a significant, negative relationship between cross‐sectional whole brain CVR and BGePVS (β =‐0.338, P = 0.003). Moreover, CVR in the left basal ganglia was negatively related to BGePVS in the left basal ganglia (β = ‐0.401, P < 0.001), and CVR in the right basal ganglia was negatively related to BGePVS in the right basal ganglia (β = ‐0.444, P < 0.001).ConclusionOur findings indicate a regional relationship between lower CVR and BGePVS burden, suggesting BGePVS are related to arterial stiffness. Longitudinal studies are required to address causality. Future work should compare other potential mechanisms of perivascular space enlargement to strengthen the hypothesis that arterial stiffness leads to ePVS.
Cultural adaptation and validation of the social functioning in dementia scale (SF‐DEM) in Taiwanese patients with dementia
Authors: Yu Ruan‐Ching , Sommerlad Andrew , Mukadam Naaheed , Livingston Gill 
Published: December 2022

AbstractBackgroundThe social functioning in dementia scale (SF‐DEM) is a 20‐item interviewer‐administered questionnaire, with patient‐ and carer‐rated versions. It was the first test designed to measure social function in people with dementia. It has not been validated in people with dementia in a Taiwanese population. We aimed to culturally adapt then validate the SF‐DEM in Taiwan and explore correlates of social functioning.MethodWe culturally adapted the SF‐DEM for Taiwan (T‐SF‐DEM) according to guidelines and tested it with people with clinically diagnosed dementia and their caregivers in Northern Taiwan We used descriptive and correlation analysis to explore how scores relate to the Clinical Dementia Rating (CDR), Addenbrooke’s cognitive examination III (ACE‐III) and Quality of Life in Alzheimer’s Disease (QoL‐AD).ResultWe recruited 12 people aged 45 to 100 with dementia (5 Alzheimer’s disease, 4 Vascular dementia, 1 Parkinson’s disease dementia, and 2 mixed. All patients and 11/12 (92%) of carers completed the SF‐Dem. Nine participants (75%) scored 0.5 on CDR and three (25%) scored 1. The mean ACE‐III score was 64.4 (standard deviation (SD) 11.9). The mean scores of patients and their carers for the sub‐domains of “spending time with other people (max 21 points)” were 3.3 (3.1) and 4.9 (3.4), for “communicating with other people (max 18)” were 5.7 (4.0) and 5.4 (3.8), for “sensitivity to other people (max 12)” were 10.9 (1.8) and 8.7 (2.6). The correlation between carer‐ and patient‐ratings was low (r = 0.33). There was a moderate correlation of the carer‐rated SF‐DEM with ACE (r = 0.66) and carer‐rated quality of life (r = 0.44). Seventy‐five percent of patients stated that they did not want to change their social life, while 100% of the carers stated they would like the patients’ social life to change.ConclusionThe T‐SF‐DEM is an acceptable test for measuring social function in Taiwanese populations in memory clinic settings. Patients scored low on social contact as they were isolated due to the pandemic. We will test SF‐DEM in more patients and report the results.
Mild behavioral impairment is associated with plasma p‐tau181 in a dementia‐free population
Authors: Ismail Zahinoor , Ghahremani Maryam , Chen Hung‐Yu , Wang Meng , Zetterberg Henrik , Smith Eric E. 
Published: December 2022

AbstractBackgroundMild behavioral impairment (MBI) is a validated neurobehavioral syndrome describing emergent and persistent neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. In cognitively normal older adults MBI is associated with positron emission tomography and cerebrospinal fluid measured amyloid‐β and tau, the characteristic hallmarks of Alzheimer’s disease (AD). Plasma p‐tau181 is a blood‐based biomarker recently identified as an accessible alternative for in‐vivo detection of AD pathologies. So far, no study has explored plasma p‐tau181 in MBI. Here, we investigated the cross‐sectional and longitudinal associations of MBI with plasma p‐tau181 in dementia‐free older adults, and the associations of MBI with risk of AD.MethodThe sample included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who were cognitively unimpaired (CU) or had mild cognitive impairment (MCI). MBI status was determined using NPS total score at baseline and year‐one. NPS scores were derived from the Neuropsychiatric Inventory and categorized as persistent NPS (i.e., MBI, score>0 at both visits); transient/impersistent NPS (score>0 at only one visit); and no NPS (score = 0 at both visits). Cross‐sectionally, linear regression models were fitted with p‐tau181 as dependent variable and NPS profile as independent variable. Longitudinally, Cox proportional hazards models examined associations between NPS profile and incident dementia. Multilevel linear mixed effect (MLME) models assessed the associations between NPS status, categorized as within‐person NPS variability (impersistent NPS, not consistent with MBI) and between‐person NPS burden (persistent NPS, consistent with MBI), and p‐tau181 across four years.ResultThe final sample consisted of 571 dementia‐free participants (age 72.2, 46.8% females). Compared to no NPS, participants with persistent NPS but not transient NPS had higher baseline plasma ptau‐181 levels. Longitudinally, persistent NPS were associated with 3.42 times greater risk for dementia compared to no NPS. MLME analyses on annual measures of NPS and p‐tau181 over four years demonstrated that only the between‐person NPS measure was associated with higher p‐tau181 levels.ConclusionThese findings extend the evidence base that MBI is a clinically relevant syndrome associated with the AD pathophysiological process. Incorporating MBI into clinical screening may help to identify those with preclinical or prodromal AD.
The effect of socioeconomic status on cognitive and socioemotional processes in Latin American older adults
Authors: Migeot Joaquín , Calivar Mariela , Granchetti Hugo , Ibáñez Agustin , Fittipaldi Sol 
Published: December 2022

AbstractBackgroundSocioeconomic status (SES) negatively impacts cognitive and executive functioning in older adults, yet its effects on socioemotional abilities have not been studied in this population. Also, evidence on neurocognitive processes associated with aging primary comes from Western, educated, industrialized, rich, and democratic (WEIRD) populations, hindering the generalization of findings to those from upper‐middle‐ and low‐middle‐income countries, such as Latin America.MethodHere, we compared the performance of low‐ and high‐SES older adults from Argentina in cognitive state, executive functions, social cognition (emotion recognition and theory of mind), and counter‐empathic social emotions (envy and Schadenfreude; displeasure at others’ fortune and pleasure at others’ misfortune, respectively). Subsequently, we developed a path analysis to test the directionality of the relationship among those variables in a theoretically plausible model and tested the main paths via multiple regression analyses.ResultRelative to the high‐SES group, low‐SES older adults showed markedly poorer performance on all assessed domains. Convergent evidence from covariance, multiple regression, and path analyses suggested that SES impact on socioemotional processes was not primary but mediated by cognitive and executive decline.ConclusionThese findings offer the first characterization of SES impacts on cognitive and socioemotional processes in non‐WEIRD population and have relevant equity‐related implications for brain health.
Feasibility and reliability of telephone‐based cognitive assessment in middle‐aged and older adults in the Wisconsin Alzheimer’s Disease Research Center
Authors: Thor Yer , Basche Kristin E , Wahoske Michelle L , Spalitta Alice , Chin Nathaniel A. , Gleason Carey E. , Clark Lindsay R. 
Published: December 2022

AbstractBackgroundUse of telephone‐based cognitive assessments became more widespread during the COVID‐19 pandemic. The National Alzheimer’s Coordinating Center (NACC) developed the telephone‐based cognitive battery (T‐Cog) to ensure continued data collection and participant retention. The objective of this study was to (1) assess the feasibility and reliability of T‐Cog data collected during the pandemic, (2) evaluate these data in the context of prior in‐person data and (3) inform future use of remote data collection.MethodThe Wisconsin ADRC Clinical Core staff administered T‐Cog batteries to participants with normal cognition, mild cognitive impairment (MCI), or dementia (n = 380, mean age = 68.7±8.9, 66.1% female, 78.4% white, mean education = 16.2±2.48) (Table 1). Examiners rated the validity of the testing session and noted reasons for an invalid session. Reliability was assessed by comparing individual neuropsychological test performances from the T‐Cog to the most recent in‐person evaluation using intraclass correlation coefficients (ICC). Chi‐square was used to test if research diagnoses (normal cognition, MCI, dementia) varied by modality (T‐Cog, in‐person).ResultsMost T‐Cog sessions were rated as valid by examiners (87.8%). The most common reasons for questionable or not valid session included hearing impairments, distractions, and interruptions (Figure 1). Measures of verbal fluency (Animal Naming (ICC = 0.69), F+L Fluency (ICC = 0.73)), list‐learning and memory (RAVLT Trials 1–5 (ICC = 0.75), RAVLT Long Delay Recall (ICC = 0.70), RAVLT Recognition (ICC = 0.71)), and story memory (Craft Story‐Immediate (ICC = 0.65), Craft Story‐Delayed (ICC = 0.73)) showed moderate to excellent reliability and were significant (p<0.01), suggesting good agreement between T‐Cog and in‐person assessments (Table 2). Measures of attention (Digit Span Forward (ICC = 0.66), Digit Span Backward (ICC = 0.15)) varied from moderately reliable to not reliable, respectively. Lastly, research diagnoses did not differ by testing modality.ConclusionThese results suggest T‐Cog assessments are feasible for participants who cannot complete in‐person visits, given adequate hearing and limited distractions and interruptions to ensure test validity. Preliminary comparisons of T‐Cog vs in‐person performances suggest good reliability for verbal fluency, story memory, and list‐learning measures. Although remote assessments can expand access and diversify the population involved in AD research, identifying assessments that are both feasible and reliable across varied administrations will be essential to track longitudinal change in cognitive status.