bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip‐palate cleft: A case report and expansion of the phenotype
Authors: Papingi Dzhoy , Bierhals Tatjana , Volk Alexander E. , Kutsche Michael , Paul Kevin , Herget Theresia 
Published: December 2023

AbstractBiallelic pathogenic variants in the TTC26 gene are known to cause BRENS (biliary, renal, neurological, skeletal) syndrome, an ultra‐rare autosomal recessive condition with only few patients published to date. BRENS syndrome is characterized by hexadactyly, severe neonatal cholestasis, and involvement of the brain, heart, and kidney, however the full phenotypic and genotypic spectrum is unknown. Here, we report on a previously undescribed homozygous intronic TTC26 variant (c.1006‐5 T > C) in a patient showing some of the known TTC26‐associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy, and congenital heart defect. Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip‐palate. The variant is considered to affect correct splicing by the loss of the canonical acceptor splice site and activation of a cryptic acceptor splice site. Hereby, our patient represents one additional patient with BRENS syndrome carrying a previously unreported TTC26 variant. Furthermore, we confirm the involvement of the pituitary gland to be a common clinical feature of the syndrome and broaden the clinical spectrum of TTC26 ciliopathy to include facial clefts and a probable hearing involvement.
Effect of landscape attributes on the occurrence of the endangered golden‐headed lion tamarin in southern Bahia, Brazil
Authors: Teixeira Joanison Vicente dos Santos , Bonfim Fernando César Gonçalves , Vancine Maurício Humberto , Ribeiro Milton C. , Oliveira Leonardo de C. 
Published: December 2023

AbstractThe golden‐headed lion tamarin (Leontopithecus chrysomelas) is an endangered primate that occurs exclusively in the Atlantic Forest of southern Bahia, Brazil. Its geographic range has been severely reduced by deforestation and its populations are restricted to a human‐modified landscape consisting primarily of Atlantic forest fragments and shade cacao (Theobroma cacao) agroforestry, locally known as cabrucas. In the last 30 years, there has been a 42% reduction in the geographic range and a 60% reduction in the population size of L. chrysomelas, with only 8% of its habitat represented by protected areas. Thus, we investigated the occurrence of L. chrysomelas in forest fragments and cabrucas based on interviews and using playback census, and evaluated the influence of landscape attributes on its occurrence. The occurrence was measured using a Generalized Linear Model using a set of 12 predictor variables, including fragment size and elevation. L. chrysomelas inhabited 186 (38%) of the 495 forest fragments and cabrucas. Most inhabited habitat patches (n = 169, 91%) are in the eastern portion (ca. 70 km wide region from the Atlantic coast to inland) of its geographic range. The remaining (n = 17, 9%) are in the western portion of the distribution, between 70 and 150 km from the Atlantic coast. Our models indicate a higher occurrence of L. chrysomelas in the eastern portion of its geographic range, where the landscape exhibits lower land cover diversity, greater functional connectivity, lower altitudes (<400 m), and is primarily composed of forest fragments and cabrucas with a higher core percentage. In contrast, we observed a lower occurrence of L. chrysomelas in the western portion, where the landscape is more diverse and heterogeneous due to anthropogenic activities, such as agriculture and livestock. We urge the establishment of ecological corridors via reforestation of degraded areas in the western portion of the range. This increase in habitat availability and suitability in the west together with the protection of the forests and cabrucas in the east would increase our chances of saving L. chrysomelas from extinction.
Age‐related changes in hematological biomarkers in common marmosets
Authors: Hickmott Alexana J. , Cervantes Lidia , Arroyo Juan Pablo , Brasky Kathy , Bene Michael , Salmon Adam B. , Phillips Kimberley A. , Ross Corinna N. 
Published: December 2023

AbstractResearchers and veterinarians often use hematology and clinical chemistry to evaluate animal health. These biomarkers are relatively easy to obtain, and understanding how they change across healthy aging is critical to clinical care and diagnostics for these animals. We aimed to evaluate how clinical biomarkers from a chemistry profile and complete blood count (CBC) change with age in common marmosets (Callithrix jacchus). We assessed blood samples collected during routine physical exams at the Southwest National Primate Research Center and the University of Texas Health San Antonio marmoset colonies from November 2020–November 2021. We found that chemistry and CBC profiles varied based on facility, sex, and age. Significant changes in albumin, phosphorus/creatinine ratio, albumin/globulin ratio, amylase, creatinine, lymphocyte percent, hematocrit, granulocytes percent, lymphocytes, hemoglobin, red cell distribution width, and platelet distribution width were all reported with advancing age. Aged individuals also demonstrated evidence for changes in liver, kidney, and immune system function compared with younger individuals. Our results suggest there may be regular changes associated with healthy aging in marmosets that are outside of the range typically considered as normal values for healthy young individuals, indicating the potential need for redefined healthy ranges for clinical biomarkers in aged animals. Identifying animals that exhibit values outside of this defined healthy aging reference will allow more accurate diagnostics and treatments for aging colonies.
Determining the minimal clinically important difference for the questionnaire of olfactory disorders in people with cystic fibrosis and factors associated with improvement after highly effective modulator therapy
Authors: Miller Jessa E. , Taylor‐Cousar Jennifer L. , Overdevest Jonathan B. , Khatiwada Aastha , Mace Jess C. , Alt Jeremiah A. , Bodner Todd E. , Chowdhury Naweed I. , DiMango Emily A. , Eshaghian Patricia H. , Getz Anne E. , Gudis David A. , Han Ethan J. , Hwang Peter H. , Keating Claire L. , Khanwalkar Ashoke , Kimple Adam J. , Lee Jivianne T. , Li Douglas , Markarian Karolin , Norris Meghan , Nayak Jayakar V. , Owens Cameran , Patel Zara M. , Poch Katie , Schlosser Rodney J. , Smith Kristine A. , Smith Timothy L. , Soler Zachary M. , Suh Jeffrey D. , Tervo Jeremy P. , Turner Grant A. , Wang Marilene B. , Saavedra Milene T. , Beswick Daniel M. 
Published: December 2023

AbstractIntroductionOlfactory dysfunction (OD) is common among people with cystic fibrosis (PwCF). The Questionnaire of Olfactory Disorders (QOD) is a validated instrument that evaluates olfactory‐specific quality‐of‐life. The QOD minimal clinically important difference (MCID) and factors associated with olfactory improvement after elexacaftor/tezacaftor/ivacaftor have not been determined for PwCF.MethodsProspective observational data were pooled from three studies that enrolled adult PwCF with chronic rhinosinusitis (CRS). QOD scores and disease characteristics were assessed. To evaluate internal consistency and calculate the QOD MCID, Cronbach's alpha and four distribution‐based methods were employed. For participants who enrolled prior to elexacaftor/tezacaftor/ivacaftor, QOD scores were obtained at baseline and after elexacaftor/tezacaftor/ivacaftor initiation. Multivariable regression was used to identify factors associated with QOD improvement.ResultsOf 129 PwCF included, 65 had QOD scores before and 3–6 months after starting elexacaftor/tezacaftor/ivacaftor. Mean baseline QOD score was 6.5 ± 7.9. Mean Cronbach's alpha was ≥0.85. The MCID estimates were as follows: Cohen's effect size = 1.6, standard error of measurement = 2.5, ½ baseline standard deviation = 4.0, and minimal detectable change = 6.9. Mean MCID was 3.7. Of those with pre/post elexacaftor/tezacaftor/ivacaftor QOD scores, the mean change in QOD was −1.3 ± 5.4. After elexacaftor/tezacaftor/ivacaftor, QOD improvement surpassed the MCID in 22% of participants (14/65). Worse baseline QOD scores and nasal polyps were associated with improved QOD scores after elexacaftor/tezacaftor/ivacaftor (both p < 0.04).ConclusionThe QOD MCID in PwCF was estimated to be 3.7. Elexacaftor/tezacaftor/ivacaftor led to qualitative but not clinically meaningful improvements in QOD score for most PwCF; PwCF with worse baseline QOD scores and nasal polyps improved in a clinically significant manner.
Human postmortem studies as a driver of biomarker development
Authors: Cobos Inma 
Published: December 2023

AbstractRecent technologies utilizing human postmortem tissue from donors who died with Alzheimer’s disease (AD) and related dementias are advancing our understanding of disease pathogenesis and progression. In this perspective session, I will present recent discoveries from single‐nuclear RNA‐sequencing, spatial multiomics, and the profiling of tangle‐bearing neurons from the human AD brain and their potential and limitations for biomarker discovery.
On the role of neuropsychiatric symptoms as markers for Alzheimer´s disease in an era of disease modifying treatments
Authors: Johansson Maurits 
Published: December 2023

AbstractEarly and reliable detection of Alzheimer’s disease (AD) is fundamental in an era with novel disease modifying treatments on the market. Late in life emerging neuropsychiatric symptoms (NPS) (e.g., apathy, anxiety, depression) have been reported prevalent among cognitively unimpaired (CU) older adults, as well as among patients with Mild Cognitive Impairment (MCI). Findings have indicated that NPS can emerge prior to MCI in ∼50% of cases that subsequently develop a neurocognitive disorder (NCD). Additionally, ∼30% of AD patients have been reported to have received a primary psychiatric diagnosis before their final NCD diagnosis. Combined, these studies point to NPS as important early clinical manifestations of AD. NPS have furthermore been related to several clinically negative outcomes, such as reduced quality of life, increased caregiver burden and earlier institutionalization. Some reports even indicate that NPS can be stronger related to these outcomes than cognition. Importantly, several studies have demonstrated NPS to be predictive of future cognitive decline, dementia, or AD. For example, anxiety in non‐demented subjects has consistently been shown to interact with beta‐amyloid yielding accelerated cognitive decline. NPS are further demonstrated related to AD neuropathological changes including beta‐amyloid, tau, and neurodegeneration. For instance, beta‐amyloid in initially CU elderly has been demonstrated associated with steeper development of NPS over time. Intriguingly, an earlier study has reported the overall burden of NPS to precede memory deficits in its association with early tau deposition in amyloid‐beta positive CU subjects, results supportive of NPS as early markers of dementing biochemical processes. Despite this growing evidence of being both prevalent and early prognostic markers, as well as associated with AD pathology, NPS are only given diminutive consideration in contemporary clinical AD diagnostic criteria. Perhaps so since the added value of NPS in such criteria has rarely been investigated. Consequently, CU subjects with a positive NPS and biomarker status face the risk of not being eligible for a disease modifying treatment since they formally do not fulfill diagnostic criteria for AD. Hence, studies exploring the added value of NPS in clinical diagnostic criteria for AD are prompted.
Comorbid Chronic Conditions and Subjective Cognitive Decline‐ A Snap‐shot
Authors: Gupta Sangeeta 
Published: December 2023

AbstractBackgroundRapidly increasing aging population in Delaware forecasts not only an increased burden of Alzheimer’s disease and related dementias (ADRD) but also a sharp rise in comorbid chronic conditions. Estimating the burden and characteristics of this “dual burden” is critical. Subjective Cognitive Decline (SCD)—a population‐based measure‐ was used to measure ADRD. The primary objective was to study prevalence of selected chronic conditions among Delaware adults with SCD in order to compare the prevalence of chronic conditions among people with and without SCD.MethodData for Delaware were obtained from the 2020 Behavioral Risk Factor Surveillance System. Respondents aged 45 years or older who answered the SCD screening question as “yes” or “no” were included in the analyses. Participants were identified as having a diagnosed chronic disease if they had been told by a doctor or other health care provider that they ever had angina; arthritis; asthma; cancer; chronic kidney disease; chronic obstructive pulmonary disease; diabetes; heart attack; and stroke. Descriptive statistics examined sociodemographic characteristics and chronic conditions in Delawareans with and without SCD.ResultNearly 1 in 12 of Delaware adults reported SCD. Compared with those without SCD, Delawareans with SCD were two or three times more likely to have angina, heart attack, stroke, diabetes, asthma, COPD, cancer, arthritis, or kidney disease. Nearly eighty percent of Delawareans with SCD have at least one other chronic health condition. More than seventy ‐five percent of Delawareans with SCD were two times as likely to have any one of the selected chronic conditions as compared to those without SCD. Adults with comorbid chronic conditions and SCD were more likely to report functional limitations.ConclusionBy 2030 the proportion of Delawareans over 60 will nearly double. Study results can facilitate timely targeted interventions to address the burden of SCD and comorbid chronic conditions in Delaware.
The Impact of a High Fat Diet on AD‐risk Associated Genes in a Mouse Model of Alzheimer’s Disease
Authors: Belanger‐Mayer Kasey M , Smith Rachel , Pumiglia Kevin , Zuloaga Kristen L 
Published: December 2023

AbstractBackgroundOver 80% of individuals with AD have a co‐morbid metabolic disease, defined as obesity, glucose intolerance, or diabetes. Both metabolic disease and a HF diet cause the release of inflammatory factors, increases AD risk, and alters the expression of hippocampal microvascular genes. Work has increased in identifying specific networks and the genes that drive these networks in AD. We hypothesize that AD causes baseline changes in a specific cluster of genes and when a HF diet is introduced, it further drives alterations of a sub‐population of genes to drive the worsening of AD pathology.MethodMale wild type (WT) and AppNL‐F knock‐in mice were given a low fat (LF; 10% fat) or high fat (HF; 60% fat; metabolic disease model) diet for 1 month. Weekly weights and end of study visceral fat weight were taken. The hippocampus was rapidly extracted and flash frozen for bulk RNA sequencing and differential gene expression analysis.ResultOn an LF diet, AppNL‐F mice had a greater body weight gain and greater visceral fat compared to WT controls. HF diet increased body weight and visceral fat in WT mice. There was surprisingly no difference between AppNL‐F mice on a LF diet and HF diet in body weight gain and visceral fat. There were 760 significant hippocampal gene alterations between AD and WT mice. Within the WT controls on a LF vs HF diet, there were 213 gene alterations and within the AD model on a LF vs HF diet, there were 31 gene alterations.ConclusionAppNL‐F mice on both a LF and HF diet gained equivalent amounts of weight, displaying an altered metabolic profile due to AD alone. While AD alone caused most of the gene alterations, a HF diet further drove alterations in a subset of genes. This work increases our understanding of the contribution of a HF diet to metabolic disease and alterations in AD‐risk associated hippocampal genes to uncover potential modifiable targets. We are currently examining specific clusters of genes and how they are linked to AD pathology, increased inflammation, and vascular dysfunction, and sequencing hippocampal samples from female mice to examine sex differences.
Effects of applying virtual reality in Cognitive Stimulation Therapy (CST) on cognition and functional communication of people with concurrent dementia and visual impairment: An initial study
Authors: Wong Winsy Wing Sze , Tsang Hiu Tung , Luk Chun Lam , Chiu Armstrong Tat San 
Published: December 2023

AbstractBackgroundCognitive stimulation therapy (CST; Spector et al., 2003) is an evidence‐based group therapy for people with dementia. Since multi‐sensory input such as visual, auditory, and tactile stimuli is used during therapy, people with sensory deficit, e.g., visual impairment, may encounter difficulties in perceiving the stimuli presented. Meanwhile, the use of virtual reality (VR) in rehabilitation has been reported in various clinical populations, its benefits on people with concurrent visual impairment and dementia are yet to be explored. The current study aimed to investigate the effects of applying VR to CST on cognition and functional communication of individuals with concurrent visual impairment and dementia.MethodFive and seven participants with mild to moderate visual impairment completed 14 sessions of CST adopted from Wong (2018) in VR‐CST and conventional conditions, respectively. Processed magnified visual stimuli were presented via head‐mounted displays in the VR group, while stimuli used in the conventional treatment group was displayed via tablets. Participants’ performance on general cognition, different cognitive components, language functions in word and discourse levels, and their functional communication was tapped three times within two weeks prior to/right after treatment, respectively. Tau‐U statistics were applied for pre/post comparison.ResultNo significant improvement was observed in all cognitive measures in the VR‐CST group while positive changes in measures on general cognition, short‐term and working memory, and executive functions were noted in the conventional CST group. Improvements in functional communication were observed in both treatment groups while gains in word comprehension were only seen in the conventional CST group (see Table 1).ConclusionThis study demonstrated preliminary evidence for the application of VR in CST among people with concurrent visual impairment and dementia.
References:Spector, A., Thorgrimsen, L., Woods, B., Royan, L., Davies, S., Butterworth, M., & Orrell, M. (2003). Efficiacy of an evidence‐based cognitive stimulation therapy programme for people with dementia. British Journal of Psychiatry, 183, 248‐254.Wong, G. H., Yek, O. P., Zhang, A. Y., Lum, T. Y., & Spector, A. (2018). Cultural adaptation of cognitive stimulation therapy (CST) for Chinese people with dementia: Multicentre pilot study. International journal of geriatric psychiatry, 33, 841‐848.
Evaluating brain age as a marker of autosomal dominant Alzheimer disease progression
Authors: Millar Peter R , Gordon Brian A. , Benzinger Tammie L.S. , Cruchaga Carlos , Fagan Anne M. , Goate Alison , Hassenstab Jason J. , Holtzman David M. , Llibre‐Guerra Jorge J , Morris John C , Perrin Richard J. , Supnet Charlene B , Xiong Chengjie , Bateman Randall J. , Ances Beau , McDade Eric ,   the Dominantly Inherited Alzheimer Network
Published: December 2023

AbstractBackgroundEstimates of “brain‐predicted age” quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD). We used a previously‐trained model (DeepBrainNet [DBN], Bashyam et al., 2020), which requires minimal MRI pre‐processing, to predict brain age in the Dominantly Inherited Alzheimer Network (DIAN) and evaluated brain age as a marker of ADAD progression.MethodWe used DBN to predict brain age from minimally‐processed, whole‐brain T1 structural MRI scans in 265 ADAD mutation‐carriers (MCs) and 183 non‐carrier controls (NCs). We then tested whether the brain age gap (BAG; difference between predicted and true age) differed as a function of mutation and cognitive status, or estimated years until symptom onset (EYO), and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid‐β‐42/40), phosphorylated tau (CSF and plasma pTau‐181), neurodegeneration (CSF and plasma neurofilament light [NFL]), and cognition (global neuropsychological composite and CDR‐sum of boxes). Finally, we compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of mutation variants (APP vs. PSEN1 before or after codon 200), APOE E4 carrier status, sex, and education.ResultDBN accurately predicted age in DIAN (Figure 1A). BAG was elevated in symptomatic and asymptomatic MCs, compared to NCs, beginning around ‐10 EYO (Figure 1B,C). BAG, hippocampal volume, and a cortical thickness summary followed similar trajectories across EYO (Figure 1D). BAG was positively associated with PiB PET, CSF and plasma pTau, and CSF and plasma NFL, and was associated with worse cognitive scores, especially in symptomatic MCs (Figure 2). BAG was most elevated in MCs with a PSEN1 mutation before codon 200, but did not differ as a function of APOE, sex, or education (Figure 3).ConclusionWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG tracks well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, DBN‐based BAG offers unique benefits in simplicity of data processing and interpretation.
The brain‐immune ecosystem: Implications for immunotherapy in defeating neurodegenerative diseases
Authors: Schwartz Michal 
Published: December 2023

AbstractBackgroundSince Medawar and Burnet’s studies some 70 years ago, it was widely accepted that the CNS cannot tolerate any immune activity under any circumstances. Over the past two decades, my team initiated a change in this dogma, by demonstrating that the brain requires support from innate and adaptive immune cells for its maintenance and repair. Deep understanding of these relationships by our team and by others has led us to propose that the immune cells that are hosted within the brain’s borders, together with neurons and non‐neuronal cells, form an ecosystem that enhances the resilience of the brain and its robustness in withstanding continuous and diverse perturbations. Accordingly, any dysfunction in this brain‐immune communication might impact brain activity.MethodAs aging is the major risk factor in dementia, including Alzheimer’s disease, we propose that dysfunction of any aspect of the brain‐immune ecosystem could affect disease onset and severity, but could be amenable to immune intervention. This model led us to propose that defeating such diseases could be accomplished by harnessing the immune system, which is either exhausted or insufficientResultWe found that transiently blocking the inhibitory PD‐1/PD‐L1 immune checkpoint pathway, initiates an immune response in the periphery that leads to disease modification within the brain. This approach was found to be effective regardless of disease etiology, and is independent of microglial polymorphism. We found that the treatment improved cognitive performance and reduced multiple parameters that contribute to disease escalation, including neural loss, local inflammation, and phospho‐ and aggregated‐tau in tauopathy, and soluble oligomers of amyloid beta in amyloidosis. The effect was found to be dependent on bone marrow‐derived macrophages, and was also associated with homing of FoxP3 regulatory T cells. Brief intermittent treatment with an AD‐optimized antibody was found to provide long‐term effect.ConclusionTogether, these studies show that targeting the immune system provides new avenues for understanding and treating neurodegenerative diseases.