bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroinflammation in posterior cortical atrophy and typical Alzheimer’s disease
Authors: Abdi Zeinab , Yong Keir X X , Crutch Sebastian J , Schott Jonathan M , Lashley Tammaryn 
Published: December 2022

AbstractBackgroundPosterior cortical atrophy (PCA) is a neurodegenerative, predominantly young‐onset syndrome most commonly caused by Alzheimer’s disease (AD). PCA presents with visual and spatial dysfunction attributed to occipito‐parietal or “posterior” brain regions rather than memory difficulties characteristic of typical Alzheimer’s disease (tAD) attributed to medial temporal regions. Whilst the underlying pathology of PCA and tAD are usually the same: Aβ plaques and tau neurofibrillary tangles (NFTs), imaging and neuropathological work points to a more posterior distribution of NFTs in PCA. Differences in inflammatory response have been proposed to relate to AD heterogeneity evident in PCA. This study compared neuroinflammation between PCA and tAD in relation to Aβ and tau at autopsy.MethodImmunohistochemistry for microglial markers (CD68, Iba1, HLA‐DR/DP/DQ) and Aβ/tau was carried out on the frontal, parietal, temporal and occipital brain regions of 26 clinically and pathologically phenotyped PCA cases and 27 age and gender‐matched tAD cases from UCL Queen Square Brain Bank. All PCA patients had a neuropathological diagnosis of AD (Table 1). Marker load was quantified as percentage surface area of the 4 brain regions using Image J software.ResultThis study showed significantly lower temporal CD68 load in the tAD compared with the PCA group, (reduced CD68% area: ‐ 0.88%; (95%CI [‐0.42,‐1.34]), p<0.001). Frontal CD68 load was significantly lower in PCA compared with tAD, (reduced CD68% area: ‐0.54; (95%CI[‐1.01,‐0.07]), p = 0.025), see Fig 1A. Parietal tau was significantly higher in the PCA group compared with the tAD group (increased tau % area: 5.15%; (95% CI [0.55, 9.76]), p = 0.029. The highest observed tau load within the PCA group was in the frontal region and for tAD in the temporal region, see Fig 1B.ConclusionRegional increases in tau and decreases in markers of activated microglia differ between PCA and tAD. Discrepancies between tau and activated microglial markers are particularly apparent in temporal and frontal regions in tAD and PCA respectively. This may be in line with the notion of a disconnect between microglial phagocytic activity at later stages of Alzheimer’s disease leading to further accumulation of tau and subsequent neuronal death.
Functional eigenvector centrality dynamics are related to amyloid deposition in preclinical Alzheimer’s Disease
Authors: Lorenzini Luigi , Ingala Silvia , Collij Lyduine E. , Wottschel Viktor , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Chetelat Gael , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Waldman Adam , Wardlaw Joanna M , Ritchie Craig W. , Gispert Juan Domingo , Mutsaerts Henk‐Jan , Visser Pieter Jelle , Scheltens Philip , Tijms Betty M. , Barkhof Frederik , Wink Alle Meije 
Published: December 2022

AbstractBackgroundIn preclinical Alzheimer’s disease (AD), amyloid accumulates in highly‐functionally connected brain regions. This selective vulnerability is related to the high neuronal fluctuations, typical of these regions. Dynamic functional connectivity (FC) was introduced to investigate network organization over time, with high network variations indicating regional flexibility, hence promoting functional integration. The relation of early amyloid deposition with FC dynamics remains unclear. Eigenvector centrality (EC) evaluates a node's importance in functional networks, both for the whole functional MRI time series (“static” EC) or within sliding‐windows (“dynamic” EC). We studied the association of cerebrospinal fluid (CSF) amyloid load with static and dynamic EC in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort.MethodData for 701 non‐demented participants were available. CSF Aβ1‐42 levels <1000 pg/mL were defined as amyloid positive (A+) (Elecsys assay). Both static and dynamic voxel‐wise EC were computed from rs‐fMRI time series. Static EC differences between A+ and A‐ participants were assessed using linear models. Standard deviation and range of dynamic EC were compared between A+ and A‐ participants within significant clusters of static EC differences, and within 10 resting‐state networks (RSN). Linear models were used to determine interaction between amyloid and cognitive performance on dynamic EC variability (Figure 1).ResultDemographics and clinical characteristics are shown in Table 1. A+ participants showed lower static EC values in parietal and occipital clusters, and higher static EC values in a medio‐frontal cluster (Figure 2). The medio‐frontal cluster had also lower dynamic EC variability in A+ (Figure 3). The default mode (Figure 4) and the visual networks of A+ participants also showed lower dynamic EC variability (p < 0.001). Dynamic properties in the DMN and visual networks were differentially associated with cognitive domains in the A‐ and A+ groups, with lower variability found in A+ participants with higher cognitive scores (Figure 5).ConclusionWe demonstrate that early amyloid deposition affects static and dynamic EC, possibly by reducing involvement of functional hubs in different network dynamics and functional integration, thus relating to cognitive dysfunctions. Our data suggest dynamic EC as an early biomarker of the interplay between early amyloid deposition and cognitive decline.
Volumetry of the Olfactory‐Related Structure as a New Biomarker of Individuals at Risk of Alzheimer Disease? Results From the CIMA‐Q Cohort
Authors: Jobin Benoît , Frasnelli Johannes , Boller Benjamin , Group CIMA‐Q 
Published: December 2022

AbstractBackgroundHippocampal and entorhinal atrophies are used as gold‐standard biomarkers of the prodromal stage of Alzheimer's disease (AD). These atrophies are related to episodic memory deficits found in individuals with mild cognitive impairment (MCI). Olfactory deficits have been identified as clinical biomarkers of AD and found in individuals with MCI. Olfactory‐related structures such as the primary olfactory cortex (POC) were found to be atrophied in patients with AD. The aim of this study was to evaluate if the atrophy of hippocampal and entorhinal regions in individuals with MCI was accompanied with the atrophy of the POC regions.MethodUsing voxel‐based morphometry (VBM), we compared hippocampal, entorhinal and POC’s grey matter volume between a group of 93 participants with memory complaint (mean age: 72.15, SD: 4.74) and a group of 40 patients with MCI (mean age: 72.08, SD: 5.51) from the Consortium for the early identification of Alzheimer's disease–Quebec (CIMA‐Q). VBM analyses were done using the region of interest (ROI) approach with a specific mask combining masks for the hippocampus and the entorhinal cortex from the Neuromorphometrics atlas and a mask for POC structures from Northwestern University (Zhou et al., 2019).ResultVBM analysis reveals smaller bilateral grey matter volume within bilateral hippocampus (left peak: MNI ‐32 −10 ‐22, k = 24, T = 3.78, pFWE corr. = 0.033) (right peak: MNI 30 −8 ‐26, k = 111, T = 4.11, pFWE corr. = 0.016) and right POC (peak: MNI 27 0 ‐14, kE = 20, T = 3.71, pFWE corr. = 0.035) in MCI patients compared to the older participants with memory complaints.ConclusionThe neurodegeneration of olfactory‐related structures seems to occur in the prodromal stage of AD and atrophy of these structures might represent a way to improve the specificity of preclinical AD if combined with hippocampal atrophy.
The Cognitive Connectome in SCD
Authors: Gonzalez‐Burgos Lissett , Cedres Nira , Garcia‐Cabello Eloy , Diaz‐Galvan Patricia , Westman Eric , Ferreira Daniel , Barroso Jose 
Published: December 2022

AbstractBackgroundSubjective cognitive decline (SCD) in cognitively normal individuals is a relevant predictor of future cognitive decline, dementia, and neurodegeneration. Previous studies showed that the cognitive decline cannot be captured by objective neuropsychological testing in SCD. However, whether sophisticated multivariate approaches such as graph theory can potentially capture subtle cognitive abnormalities in SCD individuals is unknown. This study aimed to assess the cognitive connectome in a relatively large cohort of SCD individuals, in comparison with healthy controls (HC), and assess whether such a connectome differs in SCD across age groups.MethodWe included a total of 390 individuals, of which 211 fulfilled the core SCD criteria proposed by the international SCD Initiative (SCD‐I), and 179 individuals were classified as healthy controls. Participants were stratified into early middle‐age (37–50 years, n = 125), late‐middle‐age (51–64 years, n = 119), and elderly (65–78 years, n = 146) groups. We built cognitive networks from 47 cognitive variables separately for each age and study group using graph theory and compared the groups using global measures of average strength, average global efficiency, average local efficiency, and transitivity.ResultSCD individuals had more segregated networks in all age groups, but more prominently in the late‐middle‐age group. We observed lower within‐module connectivity in SCD individuals, in verbal memory and executive—premotor functions compared with HC. The late middle‐age SCD group showed a pattern of connectivity similar to the elderly HC group. The late‐middle‐age SCD group also showed reduced transitivity compared with the HC. We did not observe significant differences in the rest of the graph measures and in the other groups.ConclusionUsing a sophisticated multivariate approach, we demonstrate that a segregated pattern of cognitive connectivity seems to underlie SCD, particularly in individuals in the age range 51 to 64 years. After the age of 65 years, this pattern tends to be less segregated, contrary to an efficient dedifferentiation process in aging. This, together with subtle signs of brain pathology and other risk factors identified in SCD may increase the likelihood of future cognitive impairment and dementia.
Using semi‐structured interview to develop a tailored psychological intervention for individuals at risk for familial Frontotemporal dementia
Authors: Greaves Caroline V , Fearn Caroline , Stott Joshua , Rohrer Jonathan D. 
Published: December 2022

AbstractBackgroundFrontotemporal dementia is genetic in around a third of cases. Issues such as high penetrance, heterogenous symptoms and unpredictable onset may cause significant challenges for those at‐risk. Few studies have evaluated this experience and no interventions have been designed to support this group. Therefore, investigation of the at‐risk experience is required to ensure an intervention that is tailored to and appropriate for the target population, as outlined in stage 0 of the NIH stage model for Behavioural Intervention Development.MethodParticipants were individuals enrolled in UK GENFI, at‐risk of MAPT, GRN and C9orf72 mutations. Participants included those with unknown genetic status, asymptomatic mutation carriers and non‐carriers. 71 participants completed questionnaires, including GAD‐7 and PHQ‐9 measures, and the Genetic Psychosocial Risk Instrument. 16 qualitative interviews were conducted, regarding feelings experienced throughout the at‐risk journey, support needs and the genetic testing experience. An inductive approach to thematic analysis was used. Themes were then utilised to form the content of the intervention and guide design.ResultThere were no significant differences between genetic groups on GAD‐7, PHQ‐9 and GPRI measures, however 52% participants met the GPRI threshold for referral for psychosocial intervention.Key themes included: 1) Emotions experienced, 2) How risk influences how you live your life, 3) Coping, 4) Support wanted, 5) Barriers and facilitators, and 6) The importance of understanding the specific difficulties. Many participants expressed a desire for tailored psychological support facilitated by “someone who understands”.
Intervention design
The intervention applies principles largely derived from the Acceptance and Commitment Therapy model and has a blended design comprising of online sessions over eight weeks, with psychoeducational videos and three face‐to‐face sessions. There are seven to ten modules depending on the individual’s genetic status including: anxiety and low mood, rumination, survivor guilt, concern about symptom onset and uncertainty. A pilot study is currently underway and will be completed by April 2022.ConclusionLiving at‐risk of familial FTD is challenging, often requiring additional support therefore this work demonstrates the importance of NIH stage 0 research in intervention development. Future research should further explore the effectiveness of tailored interventions in at‐risk familial FTD.
Dysphagia Evaluation in a Multidisciplinary VA Cognitive Care Clinic
Authors: Mackowicz Meredith , Yee Joanne , Clark Lindsay R. , Wanninger Ellen , Lewis Brian Lee Young , Kuntz Aaron , Robison Raele , Kind Amy J. , Rogus‐Pulia Nicole M. 
Published: December 2022

AbstractThe VA Cognitive Care Clinic (CCC) provides comprehensive evaluation and longitudinal treatment for older Veterans with neurocognitive disorders and their caregivers through multidisciplinary care including geriatrics, palliative medicine, neuropsychology, and social work. Speech‐language pathology (SLP) was recently incorporated into the CCC team in response to calls for more proactive approaches to diagnosis and management of dysphagia (swallowing dysfunction) in persons with dementia. While dysphagia is estimated to be highly prevalent in this population, prior work has been limited by inadequate dementia characterization. The purpose of this novel quality improvement project was to provide descriptive information regarding the occurrence of dysphagia in persons with dementia seen in CCC.CCC patients underwent comprehensive neuropsychological and geriatrics assessments that led to a multidisciplinary determination of dementia diagnosis and subtype. Validated dysphagia‐specific clinical evaluation tools included the Eating Assessment Tool (EAT‐10; dysphagia‐specific patient‐reported outcome measure), the 3‐ounce water swallow test to assess swallowing safety (aspiration risk), and the Test of Masticating and Swallowing Solids (TOMASS) to assess swallowing efficiency. A REDCap database was constructed to track CCC evaluation results and patient‐specific variables derived from the electronic health record. Descriptive statistics were calculated for dementia diagnosis, subtype, and dysphagia measures.124 patients were seen in CCC between 2017 and 2021. Eighty‐eight patients (73%) received a dementia diagnosis with the majority meeting criteria for Alzheimer's disease (53%) or mixed etiology (24%). Sixty‐eight (55%) of these patients were evaluated by an SLP during their initial intake appointment. Twenty of 59 patients (39%) scored 3 or higher on the EAT‐10, indicating concern for dysphagia. Twenty‐six of 64 patients (41%) failed the 3‐ounce water swallow test. Thirty‐one of 62 patients (50%) demonstrated inefficient mastication based on length of total masticatory time on the TOMASS.Findings from this initial cohort indicate that approximately one‐half of patients with dementia assessed by a SLP demonstrated clinical signs of swallowing safety or efficiency impairment. Patient report of dysphagia‐related symptoms occurred at a significantly lower rate, supporting the need for SLP services in multidisciplinary memory and geriatrics clinics to facilitate early identification of dysphagia and avoid serious dysphagia‐related consequences, including pneumonia and malnutrition.
Exploring lysosomal defects and rescue strategies for Alzheimer’s disease using human transdifferentiated neurons
Authors: Chou Ching‐Chieh , Vest Ryan , Shibuya Yohei , Prado Miguel A , Wilson‐Grady Joshua , Greicius Michael D , Finley Daniel , Wernig Marius , Wyss‐Coray Tony , Frydman Judith 
Published: December 2022

AbstractBackgroundAging is the critical factor of Alzheimer’s disease (AD), the most common neurodegenerative disease. Among the pathological changes in the brain associated with AD, protein aggregates are the characteristic pathological hallmark that is composed of misfolded and toxic proteins. A decline in lysosomal proteolytic activity has been linked to protein aggregation and neuronal death, whereas how the lysosomes become defective and exacerbate neurodegeneration in the brain of AD patients is not well understood.MethodOne of the hurdles is a lack of human neuron system to acquire deep knowledge of aging and AD. Using a powerful cell reprogramming approach, we developed a new cell model for aging and AD based on the transdifferentiation of human adult fibroblasts into cortical neurons (tNeurons) by bypassing stem‐cell stage. We leveraged cell reprogramming, quantitative proteomics, CRISPR genome editing and drug discovery techniques to achieve a better understanding of how aging and AD affect human neurons, with an emphasis on their impact on the lysosomal pathway. We further used tNeurons as a platform to identify pharmacological candidates that exert neuroprotective effect against lysosomal defects, protein aggregation and neurodegeneration in AD.ResultThe transcription factor‐mediated reprogramming approach generated >85% of tNeurons as cortical glutamatergic neurons after 35‐42 days in culture. The tNeurons retained age‐related changes in epigenetic state, DNA damage and protein homeostasis (proteostasis)(Figure 1). The AD tNeurons exhibited an increased levels of Aβ42 peptides and aberrant autophagosome‐lysosome formation in the soma and neurites. Quantitative proteomics further revealed differential expression of proteins in the endosome‐lysosome and autophagy pathway between aged and AD tNeurons. We performed phenotypic and CRISPR screens to identify pharmacological candidates that ameliorate lysosomal defects and protein aggregation in aged and AD tNeurons.ConclusionThis study is anticipated to highlight that the tNeurons provide a tractable system equipped with a capacity to capture signals of human neuronal aging and neurodegenerative diseases. The outcomes provide novel insights into the role of lysosomes in the aging and neurodegenerative process, and its therapeutic implications for AD.
Preliminary biological evaluations of first brain‐penetrant GPR119‐based radiotracer in rodents and non‐human primates
Authors: Bansode Avinash , Damuka Naresh , Krizan Ivan , Miller Mack , Bashetti Nagaraju , Kumar JV Shanmukha , Ma Tao , Shively Carol A. , Lockhart Samuel N. , Whitlow Christopher T. , Craft Suzanne , Jorgensen Matthew J. , Sai Kiran K Solingapuram 
Published: December 2022

AbstractBackgroundG‐protein‐coupled receptors (GPCRs) plays a key role in regulating glucose metabolism. While GPR119 (an important GPCR) agonists have shown potential for improving neurologic and cognitive function in patients with AD and type2 diabetes mellitus (T2DM), clinical interventions targeting GPR119 will require accurate in vivo measures such as PET imaging. We recently synthesized a series of novel piperdine analogs, identifying two analogs (T1 and T2) with high GPR119 binding potency (2‐5 nM) for PET radiochemistry. Here we report their radiochemistry and initial biological evaluations in neuronal cells, normal rodents, and monkeys (vervets).Method[18F]T1/T2 radiochemistry was performed in TRASIS‐AIO automated module following [18F]¯‐based nucleophilic substitution of corresponding precursors. [18F]T1 and T2 in vitro assays were performed in three patient‐derived cell lines with different GPR119 expression (MDM‐MD‐231<NCI‐H1716<HepG2), with and without GPR119 agonists and non‐radioactive T1/T2. Dynamic 0‐60 min brain microPET/CT imaging and biodistribution were performed in normal balb/c mice (n=4). Healthy adult female vervets (n=6, 4.5‐6.7 kg) underwent 0‐90 min brain PET imaging. Standard uptake value (SUVmax) and time‐activity curves (TACs) were calculated for whole brain PET/MR images.ResultBoth [18F]T1 and T2 were produced in high radiochemical purities (>98%) and specific activities (∼3800‐4500 mCi/µmol), decay corrected to end of synthesis. Radioactive cell uptake was lower in MDM‐MD‐231 cells (lowest GPR119 expression) and higher in HepG2 cells (higher GPR119 expression); uptake also significantly increased with GPR119 agonists and T1/T2 treatments compared to baseline. [18F]T2 showed slightly better brain uptake in mice compared to [18F]T1 (SUVmax= 0.35±0.07 Vs. 0.55±0.09 g/mL). Biodistribution of [18F]T2 (%ID/mg = 1.01±0.09) also showed high brain uptake. SUVmax (avg=2.6±0.1 g/mL) and TACs of both [18F]T1 and [18F]T2 in monkey brains demonstrated rapid distribution across BBB within 10 min and favorable clearance within 90 min of tracer injection (Fig 1).ConclusionRadiochemistry was successfully automated and optimized. Cell uptake showed direct relationships between radiotracer uptake and GPR119 expression. MicroPET imaging, biodistribution in rodents and monkey PET imaging demonstrated excellent brain uptake and favorable pharmacokinetics, indicating BBB penetration. These data suggest for the first time that [18F]T1 and T2 have potential for imaging GPR119 in brains of humans with AD or T2DM.
Impact and attitudes toward genetic counseling and testing in individuals at high risk for familial Alzheimer’s Disease.
Authors: Llibre‐Guerra Jorge J , Mora‐Henao Beatriz , Restrepo‐Fernández Carlos M , Varga‐Cuadros Gabriel A , Londoño Luz E Varela , Manco Juan D Barbaran , Aguilar Laura Ramirez , Aguillon David , Leon‐Varela Yudy M , Londoño Marisol , Quiroz Yakeel T. , Ziegemeier Ellen , McDade Eric , Bateman Randall J. , Lopera Francisco 
Published: December 2022

AbstractBackgroundPre‐symptomatic genetic testing for individuals with dominantly inherited Alzheimer’s disease (DIAD) is now attracting interest due to the existence of therapeutic trials available to this population. Although the impact and the main drivers influencing the decision to seek genetic testing have been widely studied in High‐Income Countries, these reasons remain relatively unknown in Latin America (LatAm).MethodsThis study was designed to explore attitudes toward genetic testing and the impact of finding a disease‐causing mutation for early‐onset Alzheimer’s disease. The genetic counseling sessions, included a culturally sensitive program, developed in collaboration with local experts. Asymptomatic, first‐degree relatives of patients with Alzheimer’s disease dementia from an extended Colombian family (∼300) with a presenilin 1 pathogenic variant (p. I416T) were interviewed before and after genetic testing. Pre and post genetic counseling and testing measurements included the Montgomery Depression Scale, the Zung Anxiety Rating, and Genetic Counseling Outcome Scale. Primary analyses examined change in anxiety and depression scores 3 months after disclosure using linear mixed effects models and chi‐squared tests. Secondary outcomes included short Health Anxiety Inventory and knowledge about Alzheimer disease.ResultsTwenty‐five participants were invited and enrolled in the study (Figure 1). Nineteen individuals completed the genetic counseling sessions and 8/18 (44.4%) learned their genetic status. Three months after genetic status disclosure, we found no significant differences between the group that learned their genetic status and those how did not learn their genetic status in anxiety (mean = 13.5, SD = 3.2 vs. 15.1, SD = 2.5, p = 0.2) or depression (mean = 5.4, SD = 2.3 vs mean = 8.0, SD = 6.5, p = 0.6) scores. For both groups, anxiety and depression scores remained below cutoffs for clinical concern and without significant changes relative to baseline values levels.ConclusionOur pilot study shows that a structured genetic counseling and testing protocol for individuals at‐risk of DIAD is safe and and may provide psychological benefits. Future studies should include larger cohorts and expand to other countries in LatAm.