bluuebunny/crossref_metadata_2025_split huggingface dataset:
Default mode network sub‐systems connectivity in atypical Alzheimer’s disease
Authors: Sintini Irene , Corriveau‐Lecavalier Nick , Jones David T. , Radford Jonathan Graff , Singh Neha Atulkumar , Botha Hugo , Martin Peter R. , Machulda Mary M. , Schwarz Christopher G. , Gunter Jeffrey L. , Petersen Ronald C. , Jack Clifford R. , Lowe Val J. , Josephs Keith A , Whitwell Jennifer L 
Published: December 2023

AbstractBackgroundDisruption of default mode network (DMN) connectivity is common in Alzheimer’s disease. We investigated cross‐sectional and one‐year longitudinal changes in DMN sub‐systems in atypical clinical presentations of AD, in relation to age and tau.MethodSixty‐four amyloid‐positive atypical AD (Aty‐AD) patients diagnosed with posterior cortical atrophy (n = 35) or logopenic progressive aphasia (n = 29) were recruited by the Neurodegenerative Research Group. Patients underwent structural and resting‐state functional MRI, and [18F]flortaucipir PET at baseline and one‐year follow‐up. 140 amyloid‐negative cognitively unimpaired (CU) individuals from the Mayo Clinic Study of Aging were included as controls. Global tau SUVR was calculated in a meta‐ROI including parietal, temporal, and occipital regions. DMN connectivity was calculated in native space for posterior (pDMN), ventral (vDMN), anterior ventral (avDMN) and anterior dorsal (adDMN) DMN sub‐systems using the dual regression method. A global measure of DMN connectivity, the Network Failure Quotient (NFQ), was calculated as (vDMN_to_pDMN+ adDMN_to_pDMN)/(pDMN+vDMN). Linear mixed‐effects models were computed for each DMN connectivity measure, including diagnosis (Aty‐AD, CU), age, time and their interaction, and a per‐person random effect. SPM paired t‐tests were run to compare baseline and follow‐up images in Aty‐AD and CU separately. Linear mixed‐effect models were run in the Aty‐AD cohort only to investigate the effect of global baseline tau SUVR on each DMN connectivity measure.ResultMixed‐effects models showed evidence of lower cross‐sectional pDMN and higher adDMN connectivity in Aty‐AD relative to CU, with no significant time effects (Fig. 1). While connectivity in all DMN sub‐systems declined with age in CU, connectivity was higher in older Aty‐AD patients relative to younger, particularly in vDMN and pDMN. A similar trend was observed for NFQ, which was significantly higher in Aty‐AD, with a negative age effect (Fig. 1). In Aty‐AD, voxel‐based analyses showed moderate evidence of decline in vDMN connectivity and increase in avDMN connectivity over time (Fig. 2). Greater baseline global tau SUVR was associated with lower vDMN connectivity, cross‐sectionally and longitudinally (Fig. 3).ConclusionDMN connectivity was altered in Aty‐AD, with strongest alterations in younger patients. The vDMN declined over time, suggesting a shift in DMN connectivity with disease progression that was likely related to tau pathology.
SORLA‐retromer complex formation rely on receptor dimerization within the endosome
Authors: Andersen Olav M. 
Published: December 2023

AbstractBackgroundSORLA acts as an endosome recycling receptor together with the retromer complex to escort cargo through the endo‐lysosomal tubular network. SORLA is encoded by the SORL1 gene, which is the gene most frequently mutated in patients with Alzheimer’s disease, although it is still not clear which of the many variants are (the most) pathogenic. Here, we studied the biochemistry and cell biology of a SORL1 variant that is found in several European families.MethodsWe used transfected cells to study SORLA maturation and shedding of the soluble sSORLA by Western blotting. Expression of non‐mutated and mutated receptor at the cell surface was determined by flow cytometry, and the intracellular localization and overlap with markers of Endoplasmic reticulum and endosome compartments investigated by immunocytochemistry and confocal microscopy. The cellular distribution of receptor dimerization was visualized using bimolecular fluorescence complementation and proximity ligation assays, and quantified using the GFP‐trap method.ResultsWe showed that non‐mutated SORLA forms a dimer in retromer‐coated endosome structures, while the pathogenic SORLA protein is unable to form dimers, although it traffics to the endosome. This lack of dimerization in the endosome correlates with strongly decreased receptor maturation, expression at the cell surface, and shedding of its luminal sSORLA domain.ConclusionSORLA dimer formation is required for its association with retromer, which is important for efficient receptor maturation and delivery to the cell surface. Decreased cell surface expression of mutated protein with impaired dimerization leads to less shedding, showing how maturation and sSORLA production can reliably inform on the pathogenicity of SORL1 genetic variants in Alzheimer’s disease.
Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities
Authors: Cha Woo‐Jin , Yi Dahyun , Ahn Hyejin , Byun Min Soo , Jung Joon Hyung , Kong Nayeong , Jung Gijung , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young ,   KBASE Research Group
Published: December 2023

AbstractBackgroundWhite matter injury had been mostly considered a result of chronic ischemia caused by cerebral small vessel disease. However, recent studies reported that white matter degeneration could also be an important pathophysiological feature in Alzheimer’s disease (AD). This study aimed to identify the relationship between AD biomarkers, particularly amyloid‐beta (Aβ) and tau deposition, with white matter hyperintensities (WMHs) representing cerebral white matter injury.MethodA total 456 older adults aging from 55 to 90 years including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV‐1451 PET for measuring tau deposition, and MRI scans with fluid‐attenuated inversion recovery image for measuring WMH volume. For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of hemispheric white matter, inferior cerebellum and pons were used as the reference region when obtaining SUVRs. The relationships between Aβ or tau deposition and WMH volume were examined using multiple regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and baseline as well as change of WMH volume over 2 years were used as dependent variables.ResultBaseline Aβ deposition levels had significant positive association with longitudinal change of WMH volume over 2 years (β = 0.238, p = 0.009), but not with WMH volume at baseline. Baseline tau was not related with any of WMH volume at baseline and longitudinal change of WMH volume over 2 years. We also found significant interaction effect between baseline Aβ deposition level and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female (β = 0.427, p = 0.001), but not in male.ConclusionOur findings suggest that Aβ deposition, but not tau, accelerates cerebral white matter injury, particularly in female.
Multimodal MRI and tau PET findings from the Autosomal Dominant Alzheimer’s disease cohort caused by the A431E PSEN1 Jalisco mutation
Authors: Ortega Nancy E , Pa Judy , Chui Helena C , Shi Yonggang , Ringman John M 
Published: December 2023

AbstractBackgroundThe A431E mutation in PSEN1 is a cause of Autosomal Dominant Alzheimer’s disease (ADAD) that represents a founder effect, apparently arising from the state of Jalisco, Mexico, with over 100 superficially distinct families being affected. The median age of symptom onset is 41 years, with about 40% of cases having an atypical presentation of substantial spastic paraparesis. This study aimed to identify the neuroimaging features associated with the A431E PSEN1 Jalisco mutation to elucidate its pathophysiology and to inform future clinical studies.MethodThirty‐one participants with or known to be at‐risk for the A431E PSEN1 mutation were enrolled in a comprehensive genetic, clinical, and imaging protocol including MRI and flortaucipir PET scans. Diffusion MRI and flortaucipir PET studies were conducted on sub‐samples of the cohort along with appropriate control participants.ResultPeak flortaucipir standard uptake value ratio (SUVR) among A431E mutation carriers was predominantly in the lateral parietal cortices relative to the medial temporal lobes with disproportionate signal in motor and sensory cortex relative to persons with late onset AD. Flortaucipir SUVR in 6 brain regions (i.e., medial orbitofrontal, caudal and rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were associated with neuropsychiatric symptoms in persons with or at risk for the A431E PSEN1 mutation. Among 21 A431E PSEN1 mutation carriers with available diffusion MRI images, the Ashworth score of spastic paraparesis correlated with mean diffusivity in several brain regions, particularly left inferior parietal, superior parietal, and paracentral lobules (r’s>0.8, p’s< 0.001). In a subset of 10 clinically impaired A431E PSEN1 mutation carriers, mean diffusivity in white matter tracts underlying multiple cortical areas was higher relative to 8 impaired persons with late onset AD or ADAD mutations that do not cause spastic paraparesis.ConclusionThe pattern of flortaucipir distribution was atypical with disproportionate involvement of sensorimotor areas and parietal cortex. Higher flortaucipir signal was associated with more neuropsychiatric symptoms. Microstructural changes in white matter were more pronounced in persons with the A431E PSEN1 mutation and likely underlie the associated spastic paraparesis. The distinct neuroimaging features and associated neuropsychiatric manifestations observed in this cohort highlight the importance of comprehensively characterizing heterogeneous AD subtypes.
Transfusion‐dependent thalassemia patients develop cognitive impairment with gut dysbiosis
Authors: Suparan Kanokphong , Trirattanapa Kornkanok , Sriwichaiin Sirawit , Kerdphoo Sasiwan , Tantiworawit Adisak , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2023

AbstractBackgroundThalassemia is an auto‐recessive hemoglobinopathy affecting populations worldwide. Although life expectancy of thalassemia patients has been increasing due to therapeutic advancements, neurocognitive complications have been continuously reported among transfusion‐dependent thalassemia (TDT). Interestingly, the relationships among cognitive decline, systemic iron burden, and gut microbial alterations in TDT patients remain to be determined.MethodTwenty‐eight participants, including 14 TDT patients and 14 heathy controls, were recruited to evaluate a cognitive function using the Mental State Examination T10 (MSET10) test. Serum ferritin was employed to reflect a severity of systemic iron burden. Stool was collected to determine a gut microbial profile using a next‐generation sequencing of bacterial 16s rRNA V3‐V4 regions.ResultTDT patients had the cognitive impairment, higher systemic iron burden, and gut dysbiosis when compared with the controls. TDT patients also had lower MSET10 scores than the controls (Figure 1A). In addition, an increase in serum ferritin was observed in the TDT, indicating that there was the iron burden in the TDT (Figure 1B). Moreover, gut dysbiosis in TDT patients as indicated by higher bacterial diversity and different microbial compositions in comparison with the controls were observed (Figure 1C and 1D). The MSET10 scores were negatively correlated with the levels of serum ferritin and gut microbial diversity (Figure 1E and 1F). Interestingly, the levels of serum ferritin were positively correlated with the gut microbial diversity (Figure 1G).ConclusionThese findings suggest that a systemic iron burden may involve in an alteration of gut microbiota, and the systemic iron burden together with the gut dysbiosis may concurrently deteriorate a cognitive function in TDT patients. Therefore, an iron reduction with a gut microbial manipulation, such as a combined usage of an iron chelator with a probiotic supplement, should provide benefits to prevent neurodegeneration as well as gut microbial disturbance in TDT patients.
Neuropsycho‐linguistic study of agraphia and aphasia in Moroccan Arabic in patients with Alzheimer’s disease
Authors: Taiebine Mohamed 
Published: December 2023

AbstractBackgroundAgraphia and aphasia are common symptoms of neurodegenerative diseases such as Alzheimer’s disease (AD). While most studies were carried out in English, to our knowledge no study has been conducted in Arabic, to characterize these neuro‐psycholinguistic impairments in AD.MethodOur sample included 14 patients (4 with mild and 10 with moderate AD). They met the clinical criteria for AD (McKhann, 2011). The average age is 68.2 years (SD 6; 57‐77). The average number of years of education is 13 years (SD 2.9; 6‐16). The average duration of the disease is 4.2 years (SD 1.97; 1‐8) . The neurolinguistic assessment was used with Mini‐Linguistic State Examination test (MLSE, Patel et al., 2020; Taiebine et al, 2021) for the screening of language disorders. Furthermore, an exhaustive neuropsychological assessment has been carried out (global cognitive functions, memory, attention, verbal fluency, executive, praxis, and visuo‐constructional functions). The writing samples were analyzed using the MMSE sentence writing and MLSE writing subtests.ResultStatistical analysis showed that MLSE scores were influenced by disease severity and duration, whereas education level and age had no effect. As AD progresses, additional impairments become apparent in other cognitive domains. However, the marked syntactic deterioration in MLSE, compared to other linguistic domains, is an atypical pattern, whereas syntax is generally preserved in AD. (Taiebine et al, 2021). Neurolinguistic assessment showed impairment at the macro‐ and micro‐linguistic levels in terms of functional words, verbs, cohesion, and coherence. The analysis of paragraphias showed that the most frequent errors were literal omissions with missing diacritics (36%), followed by graphomotor errors (30%) and allographic errors (10%). The allographic errors are mainly graphemic simplifications that share visuospatial similarities with target letters.ConclusionThis study offers a new perspective on the linguistic characterization of AD. Moreover, it confirms the hierarchical decline in language. The pattern of post‐graphemic disorders found in our patients was consistent with the impairment of peripheral writing buffers in Arabic: graphemic, graphomotor, and allographic.
The neuropsychological palliative programs based on professionally oriented tests and quality of life of patients with Alzheimer’s disease
Authors: Sushko Viacheslav Viktorovich , Sushko Viktor Vasilievich 
Published: December 2023

AbstractAs a rule, in progressive memory disorders, memory impairment occurs in a certain sequence. One of the last things a person forgets is the knowledge and skills he or she acquired during his or her professional activities.We treated five women with Alzheimer’s disease aged 65‐70 years old. They received standard medication according to medical standards for the treatment of Alzheimer’s disease. They also received daily palliative care based on neuropsychological programs that included a variety of psychological tests and professionally oriented psychological tests. During history taking, patients were asked about their occupation. On special cards containing photos of objects connected with the patient’s profession, the patient found an object he or she could remember and name. This could be done once or every day before palliative neuropsychological programs. Then, during palliative sessions, a photo of this object was attached to all the numbers in this task, and the patient performed the action not just with numbers, but with the number of a particular object. For example, with the professionally oriented Schultz table, the patient, who had worked as a trolleybus driver all her life, found and showed not just numbers but the number of accumulators. As the patient recognized the photo of the battery and was able to name it correctly. And during the professional orientation of the Schultz table, we attached a picture of the battery to each digit. Also, at the end of the class, the patients answered the ten questions of the Patient Quality of Life Test.During palliative neuropsychological programs if patients could not do the test task because it was difficult for them, the next day we offered the patient to do a professionally oriented task which, as a rule, the patient did. Subjective assessment of the patient’s quality of life was higher if the patient managed to do everything. There was also a desire to stay in the class longer.
Safety and efficacy of acute ischemic stroke intervention in patients with cognitive decline: case‐control retrospective study
Authors: Naftali Jonathan , Auriel Eitan , Prado Keshet , Tzur Gal , Barnea Rani , Findler Michael , Rephaely Guy , Perlov Alin , Glik Amir , Keret Ophir 
Published: December 2023

AbstractBackgroundIndividuals diagnosed with mild cognitive impairment and dementia (MCI/Dem) are excluded from research on intervention for acute ischemic stroke; This research gap places stroke physicians worldwide in dilemmas while treating patients with cognitive decline. One example is acute stroke of large brain arteries, typically manifesting as immediate onset of severe neurological disability. Endovascular treatment (EVT), aka catheter‐base clot removal, is considered the gold‐standard treatment and when applied within hours after onset, can mitigate or reverse deficits and dramatically improve outcomes. Our goal was to evaluate efficacy and safety of EVT for acute stroke in MCI/Dem.MethodsThis is a single site retrospective study from Rabin Medical Center,2019‐2021. Inclusion criteria was new onset acute large vessel stroke receiving EVT treatment, ages 18‐85 years. Pre‐stroke cognitive status was assessed using previous diagnosis, assessments in geriatric / occupational therapy clinics, nurse functional questionnaire and rehabilitation interview. Individuals were dichotomized to MCI/Dem (any severity) and unimpaired via consensus between two behavioural neurologists. The MCI/Dem group was matched to unimpaired individuals for sex, age, pre‐stroke functional independence, and stroke arterial territory, severity and time to EVT. The outcomes were retrospectively assessed 90 days after stroke and included mortality, intracranial haemorrhage, and pre to post stroke difference in the modified Rankin scale (mRS), commonly used instrument for stroke functional independence.ResultsWe identified 306 individuals with acute large vessel stroke who underwent EVT, of which 32 with pre‐stroke MCI/Dem. After matching, we saw no differences between non impaired group to MCI/Dem group in functional outcome measured by mRS change, (56% vs.53%, p = 0.8), brain hemorrhage(22% vs. 9%, p = 0.68) and mortality (25% vs. 12%,p = 0.2).ConclusionTo our knowledge this is the first study to report on EVT outcomes in individuals with MCI/Dem. Our results suggest interventions for acute large vessel stroke may have similar efficacy and safety profile in individuals with pre‐stroke MCI/Dementia and thus challenge previous recommendations to exclude them from therapy. Our data is retrospective and thus of inadequate design to suggest change to clinical guidelines. Further research on stroke interventions in MCI/Dem is urgently needed to guide day‐to‐day clinical decision making
A multi‐center pooled analysis of individual imaging data of 14,876 non‐demented participants to create normative data for total and regional white matter hyperintensity volumes to support dementia diagnosis.
Authors: de Kort Floor , Biesbroek J. Matthijs ,   Meta VCI Map consortium
Published: December 2023

AbstractBackgroundWhite matter hyperintensities (WMH) are a common manifestation of cerebral small vessel disease and a major cause of cognitive decline and dementia. Recent studies show that the cognitive impact of WMH depends on their location in strategic white matter regions. WMH are highly prevalent among asymptomatic individuals and increase with age. For dementia diagnosis, identifying patients with excessive total and regional (strategic) WMH therefore requires age‐ and sex specific norms, which are currently lacking. We aimed to obtain normative data for both total and regional WMH volumes in non‐demented community‐dwelling individuals.MethodWe harmonized individual person data from 15 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Cohorts were eligible for inclusion if participants were recruited from the population, underwent brain MRI (with availability of FLAIR and T1 sequences) and cognitive testing. Cohorts that recruited patients based on the presence of cognitive symptoms were not eligible for inclusion. Individuals fulfilling criteria for dementia were excluded. WMH were segmented and registered to the MNI‐152 template. WMH maps were used to calculate total WMH volume and regional WMH volumes in 20 pre‐specified white matter tracts. Normative data on WMH volumes were derived from observed values in 5‐years age bands and reported as cut‐off values for percentiles. All volumes are normalized WMH volumes (i.e. calculated on the MNI‐152 template).ResultWe analyzed 14,876 individuals with a mean age of 63.9 years (SD 11.9), 52% of whom were female. Median WMH volume was 2.0 mL (normalized, IQR 3.9) for the total sample. Median WMH volume increased with age, from 0.25 mL (<45 years) to 7.3 and 12.8 mL (>85 years) for men and women respectively. The table shows total WMH volume cut‐off values for percentiles, stratified for age and sex (cut‐off values for regional WMH volumes not shown due to abstract size constraints).ConclusionThis study provides age‐ and sex‐specific normative data on total and regional WMH volumes. This enables an individualized approach to interpreting total and regional WMH burden to support diagnosis in clinical practice.