bluuebunny/crossref_metadata_2025_split huggingface dataset:
18F‐PI‐2620 tau‐PET in corticobasal syndrome (ActiGliA cohort)
Authors: Brendel Matthias , Palleis Carla , Prix Catharina , Finze Anika , Boetzel Kai , Danek Adrian , Höllerhage Matthias , Beyer Leonie , Sauerbeck Julia , Rauchmann Boris , Stephens Andrew W , Drzezga Alexander , van Eimeren Thilo , Barthel Henryk , Patt Marianne , Sabri Osama , Villemagne Victor LL , Bartenstein Peter , Perneczky Robert , Haass Christian , Levin Johannes , Höglinger Günter 
Published: December 2020

AbstractBackgroundThe pathology of Corticobasal syndrome (CBS) is characterized by 4‐repeat (4R)‐tau aggregation in Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) in ∼50%, or by (3/4R)‐tau aggregation in Alzheimer’s disease (AD) in ∼25% of patients. The second generation tau‐PET ligand 18F‐PI2620 showed high affinity to 3/4R‐tau in AD and also revealed affinity to 4R‐tau pathology. The aim of this study was to investigate 18F‐PI2620 in patients with CBS that are part of the interdisciplinary AD study “Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer‘s Disease (ActiGliA)”.MethodActiGliA comprises a comprehensive clinical assessment, multimodal prospective imaging in vivo and fluid biomarker analyses. Thirty‐five patients (70±8y) with probable or possible CBS according to MDS‐PSP or Armstrong‐criteria underwent 18F‐PI2620 PET together with ten age‐matched healthy‐controls. Distribution volume ratios (DVR, 0‐60 min) of subcortical and cortical brain‐regions were generated using cerebellar reference tissue. DVR‐data were quantitatively and visually compared between CBS and healthy‐controls. Regional 18F‐PI2620 binding was compared with clinical severity (PSP rating scale, PSPRS), and disease duration. Amyloid‐PET served for assessment of β‐amyloid status.Result26% (9/35) of CBS patients (PSPRS: 25±13) were amyloid‐positive. Overall, a visually discernible 18F‐PI2620 was observed in 26 subjects (74%) and in 89% of amyloid‐positive CBS patients. Significantly elevated 18F‐PI2620 DVR was observed in the whole group of CBS patients versus healthy controls in the putamen, globus pallidus and subthalamic nucleus (Cohen’s d: 1.19/ 1.44/ 1.11, all p<0.01). The cortical signal was higher in amyloid‐positive when compared to amyloid‐negative CBS patients (DVR: 1.05±0.15 vs. 0.95±0.05, p=0.005, Figure 1). Cortical binding in CBS was heterogeneous (positive in 49%; 17/35, Figure 2). Asymmetry of PET tracer uptake matched the contralateral clinical dominance in 94% of CBS cases. 18F‐PI2620 binding showed a correlation with disease severity in the globus pallidus after controlling for age, sex and β‐amyloid‐status (R=0.426, p=0.021).ConclusionThe application of 18F‐PI2620 in the ActiGliA study shows that 18F‐PI2620 is a potential biomarker for evaluation of CBS, facilitating detection of heterogeneous neuropathology and variable cortical and subcortical deposition sites, which could serve for monitoring disease status, progression, and target engagement.
Metformin treatment attenuates tau seeding in neuritic plaques
Authors: Zhao Shuai , Chen Yanxing , Fan Ziqi , Zhang Baorong 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized by deposition of amyloid‐β (Aβ) plaques, neurofibrillary tangles. Metformin has been reported to decrease Aβ plaque load , reduce spatial memory deficit in APP/PS1 mice and reduce tau phosphorylation in the P301S mutant human tau (P301S) transgenic mouse. However, the effect of metformin on Aβ plaque‐associated tau pathogies remains unclear.MethodFemale 9‐month‐old APPswe/PS1DE9(APP/PS1) mice were used. Mice in the treatment group received 4 mg/ml metformin in the drinking water for 2 months. Brain extract containing tau aggregates isolated from P301S transgenic mouse brain was unilaterally injected into the right hippocampus and overlying cerebral cortex two weeks after the initial administration of metformin. Tau pathology, its effect on Aβ pathology and plaque‐associated microgliosis were assessed by immunohistochemical staining and immunofluorescence analysis 50 days after infusion.ResultWe observed seeded tau aggregates in dystrophic neurites surrounding Aβ plaques(NP tau) throughout the ipsilateral hippocmapus as well as spread to the contralateral hippocmapus in seeded mice using this experimental paradigm. NP tau aggregation was reduced after metformin administration. We found a decrease in the number of microglia around Aβ plaques in hippocampus of seeded mice and an increase of Aβ load in the bilateral cortex and the ipsilateral dentate gyrus of hippocampus in seeded mice. Metformin administration enhanced the activation of microglia around Aβ plaques and attenuates the Aβ load in the seeded mice.ConclusionThese findings indicate that metformin can enhance plaque‐associated microgliosis, attenuate Aβ load and peri‐plaque tau pathologies, making it a potential therapeutic treatment for AD.
Preliminary results from the Partner Availability Limitations Study (PALS)
Authors: Largent Emily A. , Clapp Justin , Sykes Olivia , Abera Maramawit , Harkins Kristin , Grill Josh D. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) clinical trials, even trials recruiting cognitively normal populations, require participants to enroll with a “study partner” (SP). SPs serve as knowledgeable informants, reporting on participants’ cognitive and functional performance. The SP requirement can be a barrier to research participation, especially if an older adult doesn’t have someone able or willing to enroll with them.MethodParticipants in this qualitative study are adults aged 60‐85 who previously signed up to participate in either the University of California, Irvine Consent to Contact Registry (C2C) or the University of Pennsylvania Brain Health Research Registry. Respondents participate in semi‐structured interviews covering: (1) social supports; (2) willingness to ask someone to be their SP; (3) whom they would ask; and (4) ways of increasing SP participation. Individuals identified as likely to be asked to be a SP are subsequently recruited to participate in semi‐structured interviews covering similar domains. Sixty potential AD trial participants and 30 potential SPs are being interviewed. All interviews are recorded, transcribed, and coded. Coding is managed with NVivo 12.0. The University of Pennsylvania IRB approved this study.ResultsMost respondents identify at least one person—typically a family member or close friend—who could be their SP. When identifying a potential SP, respondents consider their relationship with and personal traits of the SP, as well as the logistics of research participation. Willingness to ask that individual to fill the SP role varies. The SP role is seen as burdensome, with the relative level of burden dependent on non‐research demands on the SP’s time and attention (e.g., family and work). Respondents believe that the SP role has numerous benefits for the participant (e.g., emotional/logistical support), the SP (e.g., positive feelings), and the researchers (e.g., additional source of data). Offers of payment to the SP and flexible study visits (e.g., nights/weekends or virtual appointments) would increase willingness to ask a SP.ConclusionOur results indicate that identifying someone able and willing to serve as a SP can be challenging for older adults interested in AD clinical trials, but modifications of study design may help overcome this barrier.
Inflammatory markers in Alzheimer's disease and mild cognitive impairment: A meta‐analysis and systematic review of 170 studies
Authors: Shen Xue‐Ning , Niu Li‐Dong , Wang Yanjiang , Cao Xi‐Peng , Liu Qiang , Tan Lan , Zhang Can , Yu Jin‐Tai 
Published: December 2020

AbstractBackgroundInflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD and MCI quantitatively.MethodStudies reporting concentrations of peripheral or cerebrospinal fluid (CSF) markers were included, and eligible data on AD, MCI and control were extracted. Pooled Hedges's g was adopted to illustrate comparisons, and various confounding factors were used to explore sources of heterogeneity.ResultA total of 170 studies were included in the meta‐analysis and systematic review, which demonstrated increased peripheral levels of high‐sensitivity C reactive protein (Hedges's g 0.281, p<0.05), interleukin‐6 (IL‐6) (0.429, p<0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p<0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p<0.005), alpha1‐antichymotrypsin (α1‐ACT) (1.217, p<0.005), IL‐1β (0.615, p<0.05) and soluble CD40 ligand (0.868, p<0.005), and CSF levels of IL‐10 (0.434, p<0.05), monocyte chemoattractant protein‐1 (MCP‐1) (0.798, p<0.005), transforming growth factor‐beta 1 (1.009, p<0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p<0.001), YKL‐40 (0.849, p<0.001), α1‐ACT (0.638, p<0.001), nerve growth factor (5.475, p<0.005) and visinin‐like protein‐1 (VILIP‐1) (0.677, p<0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p<0.05), IL‐6 (0.129, p<0.05) and MCP‐1 (0.779, p<0.05) and lower levels of IL‐8 (‐1.293, p<0.05) in the periphery, as well as elevated concentrations of YKL‐40 (0.373, p<0.05), VILIP‐1 (0.534, p<0.005) and sTREM2 (0.695, p<0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p<0.05) and sTNFR2 (0.254, p<0.05) levels were observed in AD compared with MCI.ConclusionSignificantly altered levels of inflammatory markers were verified in comparison between AD, MCI and control, supporting the notion that AD and MCI are accompanied by inflammatory responses in both the periphery and CSF.
Menopausal hormone therapy has beneficial effects on cognitive trajectories among homozygous carriers of the APOE‐ε4 allele
Authors: Mahoney Emily R. , Dumitrescu Logan , Maki Pauline M. , Rapp Stephen R. , Keene C. Dirk , Corrada Maria M.M. , Hayden Kathleen M. , Baker Laura D. , Espeland Mark A. , Resnick Susan M. , Hohman Timothy J. 
Published: December 2020

AbstractBackgroundTwo‐thirds of Alzheimer’s disease (AD) cases are females and increasing evidence suggests the greatest genetic risk factor for AD, the APOE‐ε4 allele, has a stronger association among females compared to males. Estrogen changes after menopause may contribute to cognitive decline, particularly among those at highest genetic risk for AD. While estrogen treatment has not shown a consistent association with reducing cognitive decline in late‐life, the modifying role of APOE on the cognitive consequences of menopausal hormone therapy (MHT) is not well‐characterized. We used a pharmacogenomic approach to evaluate the interaction between MHT and APOE on longitudinal cognitive change leveraging data from the Women’s Health Initiative (WHI).MethodWe evaluated data from 4,128 WHI participants who were randomized to receive conjugated equine estrogens with or without medroxyprogesterone acetate (n=2,030) or matching placebo (n=2,098). Cognition was measured biennially with the Modified Mini‐Mental Status Exam (3MSE). At baseline, average age was 70±4, average 3MSE was 96±3 and 25% of participants were APOE‐ε4 carriers. Mixed‐effects regression using a three‐way interaction (APOE x years from baseline x treatment group) assessed the potential modifying role of APOE on the cognitive consequences of MHT. Separate sensitivity analyses were run in the estrogen and estrogen+progestin treatment groups.Result
APOE genotype significantly interacted with MHT on change in 3MSE scores (Figure 1, p=0.01), whereby homozygous ε4 carriers showed a benefit of MHT (p=0.01), while heterozygotes and non‐ε4 carriers showed none (p>0.07). This interaction was consistent between the estrogen‐alone and estrogen+progestin treatment groups.ConclusionMHT may have cognitive benefits among women who are at high genetic risk for AD. Literature on the cognitive effects of MHT among APOE‐ε4 carriers remains mixed, but this analysis of a large sample from a randomized trial of MHT adds critical information to the field. Additional work is needed to better understand how age, timing of MHT initiation, treatment duration and form, or other health conditions may contribute to the observed effect of MHT among APOE‐ε4 homozygotes. Regardless, these findings underscore the potential benefit of a precision medicine approach that integrates genetic modifiers of treatment response into clinical decision‐making.
Serum neurofilament light level in the clinical diagnosis of Chinese patients with Alzheimer’s disease
Authors: Chu Leung Wing , Pan Yining , Li Siwen , Chen Ruijun , Wong Dana , Song Youqiang 
Published: December 2020

AbstractBackgroundBiomarkers are much needed to assist the clinicians in the diagnosis of Alzheimer disease (AD). Neurofilament light chain (NfL) was reported as a promising blood biomarker to detect neurodegeneration in Alzheimer's disease (AD) in previous Caucasian studies. In this study, we aimed to evaluate the diagnostic accuracy of the serum neurofilament light (NfL) level in the clinical diagnosis of Chinese patients with Alzheimer’s Disease.MethodWe performed a nested case‐control study on Alzheimer’s disease patients and cognitively normal older adults, who were recruited in a prospective cohort on aging and dementia in Hong Kong in 2004‐2005. Alzheimer’s disease (AD) was diagnosed in accordance to the National Institute of Neurological and Communicative Disorders and Stroke / Alzheimer’s Disease and Related Disorders Association (NINCDS‐ADRDA) criteria. Normal control subjects had normal cognition without cognitive complaint or impairment on assessment. Blood samples were immediately processed and serum samples were stored in cryotubes in ‐80°C freezers. The serum samples of subjects were retrieved for assay of serum neurofilaments light (NfL) chain assays, using a highly sensitive single molecule array assay (SIMOA) with the Quanterix SIMOA HD‐1 Analyzer. For matching of APOE4 (with 1 or 2 copies of APOE4) status, we randomly selected 50% APOE4 positive and 50% APOE4 negative subjects.ResultThree subjects who had inadequate serum were excluded. Finally, 149 subjects (75 AD and 74 normal control) subjects were included‐ (Table). AD subjects were significantly older (p<0.001). less educated (p<0.001), and had lower Mini‐Mental State Examination (MMSE) scores (p<0.001). Age showed a positive correlation with the serum NfL level (r=0.56, p<0.001). Multivariate analyses with general linear model showed the serum NfL level was significantly higher in AD than normal control, after adjustment for age, sex and APOE. Receiver Operating Characteristic (ROC) curve analyses showed the Area‐Under‐Curve (AUC) was 0.859 (p<0.001). The optimal cut‐off of the serum NfL level for the diagnosis of AD was >17.31 pg/ml, with sensitivity and specificity of 89% and 73% respectively.ConclusionIn this study, we found the serum NfL level is a useful blood biomarker for the diagnosis of Alzheimer’s Disease in Chinese persons.
Cognitive impairment under treatment with second‐ and third‐generation antihistamines
Authors: Adler Georg , Baumgart Nadja 
Published: December 2020

AbstractBackgroundBrain histamine is involved in the regulation of arousal, cognition, and memory mainly through interactions with histamine H1 receptors. Histamine H1 antagonists often prescribed for treatment of allergic disorders, may induce sleepiness and cognitive deficits. Sedation as a consequence of treatment with 1st generation antihistamines has led to the development of 2nd and 3rd generation anthistamines, which are thought to be free of cognitive side effects. This proved to be true in studies on the cognitive effects of single doses in healthy volunteers. However, the relationship between treatment with 2nd or 3rd generation antihistamines and cognitive performance so fas has not been examined within a naturalistic study under everyday conditions. This may be relevant for Alzheimer’s disease treatment studies, because cognitive side effects as a consequence of treatment with 2nd or 3rd generation antihistamines may act as a confounding variable.Method380 patients with chronic spontaneous urticaria (CSU) were assessed in 30 dermatological practices and outpatient clinics in Germany. Severity of disease was assessed by means of the Urticaria Activity Score (UAS‐7) and the Urticaria Control Test (UCT), quality of life by the Dermatology Life Quality Index (DLQI) and the Chronic Urticaria Quality of Life Questionnaire (CU‐Q2oL). Cognitive performance was studied by means of the computer‐based Memory and Attention Test (MAT). Sociodemographic data, current medication in treatment categories, comorbidities, obesity, smoking and drinking habits are taken by a questionnaire.ResultThe assessments were carried out in 380 subjects at ages between 19 and 73 years (mean +/‐ SD: 49 +/‐ 15). In patients under treatment with 2nd or 3rd generation anthistamines compared to patients not under treatment with antihistamines, we found a significant impairment of episodic working memory, particularly in the elder subjects. The impairment was found independently whether antihistamines were applied at dosages licensed for treatment or at higher dosages. Episodic short‐term memory and selective attention were unimpaired.ConclusionTreatment with 2nd or 3rd generation antihistamines may be associated with cognitive impairment, particularly in elderly patients. This effect should be considered regarding the handling of concomitant medications in Alzheimer’s disease treatment trials.
Characteristics and prognosis of patients with mild cognitive impairment by cerebrospinal fluid biomarker profiles
Authors: Estellés Teresa , Carmona‐Iragui Maria , Illán‐Gala Ignacio , Barroeta Isabel , Sánchez‐Saudinós Maria Belen , Sala Isabel , Morenas‐Rodríguez Estrella , Altuna Miren , Santos‐Santos Miguel A , Xucla Tomás , Blesa Rafael , Fortea Juan , Lleó Alberto , Alcolea Daniel 
Published: December 2020

AbstractBackgroundBiomarkers have an important diagnostic and prognostic value in neurodegenerative diseases, especially in early stages. We analyzed the differences in baseline characteristics and clinical evolution of patients with mild cognitive impairment (MCI) according to their cerebrospinal fluid (CSF) Alzheimer Disease biomarkers profile.MethodWe retrospectively selected all patients evaluated in the Sant Pau Memory Unit that had a neuropsychological evaluation compatible with MCI, analysis of Alzheimer CSF biomarkers and clinical follow‐up for at least 6 months. Patients were classified applying our internal cutoffs for CSF levels of Aβ1‐42 as a marker of amyloidosis (A+/A‐) and CSF levels of pTau as a marker of Tau pathology (T+/T‐).We compared demographic characteristics, cognitive progression, and final clinical diagnoses between groups.ResultWe included 274 participants: 103 A‐/T‐, 43 A+/T‐, 40 A‐/T+ and 88 A+/T+. The mean follow‐up was 3.4 years. Patients in the A‐/T‐ group were younger (67.8 years) compared to those in the A+/T+ group (72.3 years, p=0.002). During follow‐up, the A+/T+ group showed greater global cognitive impairment (‐1.5 MMSE score/year; p <0.001)and higher risk of progression to dementia (OR=3,13, p<0.001). There were no differences in baseline neuropsychological scores between A+/T‐ and A‐/T+ groups. The proportions of patients with a final clinical diagnosis of Alzheimer's dementia (AD), Lewy body Dementia (LBD) and frontotemporal lobar degeneration related syndromes(FTLD) were 37%, 16% and 12% in the A+/T‐ group, and 25%, 10% and 5% in the A‐/T+ group, respectively. Compared to the A+/T‐ group, the A‐/T+ group had a higher proportion of patients whose final clinical diagnosis was non‐neurodegenerative or undetermined (60% vs. 35%, respectively; p=0.022) and a lower risk of progression to dementia (OR=0.37; p=0.032).ConclusionA CSF profile suggestive of AD pathophysiology is associated with greater global cognitive impairment and a higher risk of progression to dementia. Although we did not find differences in baseline neuropsychological scores between patients with positive markers of amyloidosis and those with tau pathology only, patients with amyloidosis showed a higher risk of progression to dementia in follow‐up. The benefit of using additional markers of amyloidosis and/or tau pathology in the assessment of prognosis of these patients needs to be further explored.
Grouping tau topologies in former boxers assessed by PET with 18F‐PM‐PBB3: A reappraisal of dementia pugilistica
Authors: Takahata Keisuke , Shimada Hitoshi , Kubota Manabu , Seki Chie , Tagai Kenji , Matsuoka Kiwamu , Miyata Mari , Sano Yasunori , Yamamoto Yasuharu , Saito Fumie , Mizushima Jin , Anamizu Sachiko , Kawamura Kazunori , Zhang Ming‐Rong , Muramatsu Taro , Tabuchi Hajime , Sahara Naruhiko , Mimura Masaru , Higuchi Makoto 
Published: December 2020

AbstractBackgroundAccumulation of hyperphosphorylated tau is a core feature of late‐life sequalae of mild‐repetitive traumatic brain injury (mrTBI). Brain‐bank surveys have demonstrated that chronic traumatic encephalopathy (CTE), defined as tau accumulation at the depths of cortical sulci, is a typical neurodegenerative condition associated with mrTBI exposure. In contrast, early case‐reports of dementia pugilistica (DP) in former boxers described considerable heterogeneity of late‐life neurodegenerative changes. Despite such inconsistency, topology of tau accumulation in the living brain of mrTBI patients have not been fully investigated. The present study was aimed to characterize cerebral retention patterns of 118F‐PM‐PBB3 (18F‐APN‐1607) in the former boxers.MethodThirteen former boxers (46.2 ± 11.9 years) and 15 age‐matched healthy control (HC) subjects underwent PET scans with 18F‐PM‐PBB3 and [11C]PiB. Standard uptake value ratio (SUVR) with the cerebellar gray matter as reference was calculated. Association of SUVR with neurocognitive symptoms and years of playing boxing was investigated.ResultAll subjects were [11C]PiB negative. Boxers showed higher 18F‐PM‐PBB3 accumulation than HC subjects in the gray (P = 0.0002) and white matter (P = 0.0001). There was a trend of correlation between SUVR values in the temporal cortex and years of exposure to concussions (p=0.07, r=0.40). Visual assessments revealed heterogeneity in 18F‐PM‐PBB3 retention patterns in boxers. First, the majority of boxers (7/13) demonstrated multiple 18F‐PM‐PBB3 accumulations around the depth of cerebral sulci, showing striking resemblance to previously reported tau topology of CTE. Subjects in this group tend to show severe memory impairment and depression. Second, a few boxers (3/13) showed diffuse 18F‐PM‐PBB3 accumulation, indicating some form of non‐AD tauopathy but currently unspecified. Subject in this group showed psychiatric symptoms such as psychosis and mania. Third, the other 3 boxers showed minimum 18F‐PM‐PBB3 retention regardless of clinical symptoms.ConclusionOur results indicates different forms of tau neuropathology underlying late‐sequalae of mrTBI in agreement with the classical concept of DP. These forms vary in where and how much tau accumulate, as well as in clinical features. The present study not only supports pathological heterogeneity of late‐sequalae of mrTBI, but also suggests utility of 18F‐PM‐PBB3 PET in detection of late‐life neurodegenerative diseases following mrTBI.