bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnostic accuracy of the Stricker Learning Span and Mayo Test Drive Composite for amnestic Mild Cognitive Impairment.
Authors: Stricker Nikki H. , Twohy Erin L , Albertson Sabrina M. , Christianson Teresa J. , Stricker John L , Machulda Mary M. , Karstens Aimee J , Patel Jay S , Kremers Walter K. , Hassenstab Jason J. , Jack Clifford R. , Knopman David S. , Mielke Michelle M. , Petersen Ronald C. 
Published: December 2022

AbstractBackgroundRemote assessment tools offer significant promise for aiding early detection of cognitive impairment. Mayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). We examined the diagnostic accuracy of the SLS and a MTD composite (SLS max span, SLS trials 1–5 total correct, SLS delay correct, [Symbols correct item response time*‐1]) for amnestic mild cognitive impairment (aMCI). We also explored diagnostic accuracy for a broader group that included individuals with possible MCI (pMCI; see Figure 1).MethodsParticipants were recruited from the Mayo Clinic Study of Aging for this ancillary remote study. 226 were cognitively unimpaired (CU; concordant CU diagnosis by 3 independent raters). Fifty‐six participants had possible MCI (at least 1 of 3 raters indicated MCI) and 16 had a consensus diagnosis of aMCI. Primary outcome variables were SLS sum of trials, AVLT sum of trials, Symbols correct items response time, and MTD composite. Mean difference analyses used linear model ANOVAs (alpha = .05). Receiver operating characteristic (ROC) curves were applied; we derived optimal cutoff scores based on the Youden index method.ResultsBoth aMCI and possible MCI groups showed significantly lower performance than the CU group on SLS (Hedge’s g aMCI = ‐1.72, pMCI = ‐1.04), Symbols (Hedge’s g aMCI = 1.38, pMCI = 0.64), and MTD composite (Hedge’s g aMCI = ‐1.89, pMCI = ‐1.09); see Tables 1 and 2 (all p‘s<.01 even when additionally covarying age, education, sex). Total area under the curve was high for differentiating of CU vs. aMCI (MTD Composite = 0.91, SLS = 0.91) and acceptable for CU vs. pMCI (MTD Composite = 0.77, SLS = 0.77); see Table 2. Consistent with our flexible platform, a variety of device types were used to complete remote testing (32% smartphone, 12% tablet, 56% PC).ConclusionsMTD and the SLS show high diagnostic accuracy for aMCI. MTD is a flexible, brief, and easy‐to‐use remote cognitive assessment tool with great potential for scalable use in future studies seeking to maximize inclusion of individuals with aMCI in clinical trials or for cognitive screening in clinical settings.
Phenotypic features of adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): presenting symptoms and clinical course
Authors: Papapetropoulos Spyros , Portius Angela , Zappia Samantha , Brennan Matthew , Leahy Leslie 
Published: December 2022

AbstractBackgroundALSP is an underdiagnosed, rapidly progressive, fatal autosomal dominant neurodegenerative disease caused by CSF1R gene mutations that result in microglial dysfunction. There are no published prospective studies on the natural history of ALSP. As a result, descriptions of phenotypic features of ALSP are derived from small case series and single case reports. To better understand the phenotypic characteristics of ALSP, a systematic literature review of these published case reports was performed.MethodA comprehensive, systematic literature review of the clinical and genetic features of ALSP was conducted to identify published case studies (January 1, 1980, through April 30, 2021) from a MEDLINE search using prespecified selection criteria. The search identified 76 published reports with data extracted from 274 ALSP patients and is the most extensive case series of ALSP to date.ResultThe mean±SD age (years) of onset of symptoms was 43.1±11.3, survival time (years) 6.3±4.6, and age of death (years) 52.9±10.8. The most common initial symptoms consisted of cognitive impairment (n = 113, 41.2%), behavioral and psychiatric dysfunction (n = 70, 25.6%), extrapyramidal motor abnormalities (n = 28, 10.2%), pseudo‐bulbar affects (n = 13 4.7%) and speech difficulty (n = 11, 4.0%) and confirmed the phenotypic heterogeneity of ALSP at disease onset, a major contributor to ALSP misdiagnosis. Clinical features associated with disease progression involved cognitive impairment (n = 216, 78.8%), behavioral and psychiatric dysfunction (n = 175, 63.9%), extrapyramidal motor abnormalities (n = 147, 53.7%), and pyramidal motor abnormalities, (n = 136, 49.6%). Less frequent clinical findings (each < 25% incidence) were pseudo‐bulbar symptoms, seizures and aphasia or speech difficulty.ConclusionThe findings of this systematic literature review are consistent with previous, smaller reports on the phenotype of ALSP. Since cognitive impairment, behavioral and psychiatric dysfunction, and pyramidal and extrapyramidal motor abnormalities were identified as the most frequent clinical features in this review, endpoints quantifying these symptoms should be considered in the design of future interventional trials of ALSP.
Inner blood‐retinal barrier alterations associated with vascular amyloidosis in MCI and AD patients
Authors: Shi Haoshen , Koronyo Yosef , Sheyn Julia , Mandalia Krishna , Fuchs Dieu‐Trang , Gupta Vivek K , Graham Stuart , Black Keith L , Mirzaei Mehdi , Miller Carol A , Koronyo‐Hamaoui Maya 
Published: December 2022

AbstractBackgroundBlood‐brain barrier (BBB) breakdown in Alzheimer’s disease (AD) is linked to cerebral amyloid‐beta (Aβ) accumulation and cognitive decline. Previously, we identified substantial retinal pericyte loss along with vascular amyloidosis in mild cognitively impaired (MCI) and AD patients. In double transgenic APPSWE/PS1∆E9 (ADtg) mice, we further demonstrated substantial retinal capillary degeneration and microvascular leakage in comparison to wild type (WT) mice. Here, we sought to expand our investigation of inner blood‐retinal barrier (iBRB) integrity in relation to retinal and cerebral pathological benchmarks in MCI and AD patients compared to cognitively normal (CN) controls.MethodPostmortem human eyes and brains were obtained from USC‐ADRC. Retinas were isolated from 35 AD patients, 15 MCI patients, and 20 age‐ and sex‐matched healthy controls. Retinal cross sections spanning along ora serrata to optic disc were prepared from four pre‐defined quadrants: superiortemporal, temporalinferior, inferiornasal, and nasalsuperior. Histological examination was performed by immunostaining for different Aβ alloforms, tight junctions (zonula occulden‐1, claudin‐1 and ‐5), and blood vessels (lectin). Retinal microvessels were isolated for evaluating capillary degeneration. Stereological quantifications were performed and then correlated with the respective neuropathological reports of these patients. Mass spectrometry analysis of proteins isolated from another AD and control patients’ cohort was conducted to validate our data.ResultOur preliminary results showed early and significant downregulation of zonula occulden‐1 in retinal blood vessels of MCI and AD patients compared to controls. Downregulation of this key tight junction molecule was associated with increased retinal vascular Aβ accumulation. In addition, significant deficiencies of vascular‐related proteins including smoothelin, vascular endothelial zinc finger 1 (VEZF1), catenin isoform 1 were detected in retinal homogenates from AD patients versus controls by global proteome analysis. Analysis of isolated retinal blood vessels revealed capillary degeneration along with Alzheimer’s‐relevant vascular pathology in these patients.ConclusionOur data suggested an early alteration of iBRB integrity that contributed to Aβ accumulation in retinal blood vessels, consistent with previous reports in BBB of AD patients. Our results provide new insights into AD‐related vascular pathomechanisms in the retina that can be further evaluated for retinal imaging.
Examining the effects of age and sex on tau PET binding in the absence of beta‐amyloid pathology
Authors: Gordon Brian A. , Flores Shaney , Dincer Aylin , Keefe Sarah J. , McKay Nicole S. , Hobbs Diana A. , Wisch Julie K. , Hornbeck Russ C. , Franklin Erin E. , Jack Clifford R. , Koeppe Robert A. , Xiong Chengjie , McDade Eric , van Dyck Christopher H , Klein Gregory , Pariente Jeremie , Bateman Randall J. , Morris John C. , Perrin Richard J. , Benzinger Tammie L.S. 
Published: December 2022

AbstractBackgroundTau PET imaging is an established tool for studying Alzheimer Disease but its sensitivity to primary age‐related tauopathy (PART) as well as sex effects in individuals without abnormal levels of amyloid are unknown.MethodsCross‐sectional data were collected from 2014 to 2019 in 144 cognitively normal younger, middle‐aged, and older adults free from amyloid pathology as quantified using PET. Regional values of tau PET binding were measured using flortaucipir. Statistical models examined the main effects of increasing age, sex, race, and subthreshold levels of amyloid. Secondary analyses also examined the relationship between tau PET binding and iron as measured using T2* weighted imaging and calcification as measured using CT.ResultsThere were significant positive associations between tau binding and age in 19 regions, with the largest effects seen in the inferior temporal cortex (t=4.59), caudate (t=9.58), and putamen (t=12.57). Iron as measured using T2* imaging mediated only a modest (11.9%) amount of the association between age and tau binding. Elevated tracer uptake in females was present in 23 regions in frontal, lateral parietal, and temporal regions including, most prominently the rostral middle frontal gyrus (t=7.48), superior temporal gyrus (t=5.12) and the inferior temporal gyrus (t=4.22). There were no significant effects of race or subthreshold levels of amyloid.ConclusionsTau PET is sensitive to primary effects of age in regions consistent with the neuropathological definition of PART although strong age effects in regions of off‐target binding were also present. There was a robust effect of sex, suggesting prior observations of elevated binding in women is not solely a potentiation of Alzheimer pathology but instead represents an ubiquitous phenomenon. Understand how both sex and age impact tracer binding is critical to understanding the utility of PET tracers as well as interpreting tracer values in the context of disease.
Reliability and sensitivity of two clock drawing test rubrics as screening measures for mild cognitive impairment
Authors: Kehl‐Floberg Kristen E , Marks Timothy S , Giles Gordon Muir , Edwards Dorothy Farrar 
Published: December 2022

AbstractBackgroundEarly identification of mild cognitive impairment (MCI) is critical, as MCI precipitates disability and may be a precursor to major neurocognitive disorder. The Clock Drawing Test (CDT) is a widely adopted screening measure for dementia however it is not known whether paper‐and‐pencil CDT scoring rubrics are sensitive to subtle losses consistent with MCI. We examined the reliability and sensitivity to MCI of two free‐drawn Clock Drawing Test rubrics ‐ the 10‐point Rouleau, and the 20‐point Clock Drawing Interpretation Scale (CDIS) in community‐dwelling older adults.Method345 adults enrolled in a study of functional cognition completed the Montreal Cognitive Assessment (MoCA), the Alzheimer’s Disease Cooperative Study Scale (ADCS‐ADL), and freely‐drawn clocks scored with CDIS and Roleau rubrics. We computed Cronbach’s alpha, receiver operating characteristic (ROC) analyses using the MoCA as the index measure, and one‐way ANOVAs with the ADCS‐ADL for each rubric.ResultOur sample was 74% female, 83.2% white. Mean age was 70.01 ±8.89, and mean education was 15.5 ±3.735 years. Average scores were 24.28 ±3.44 (MoCA), 74.85 ±4.16 (ADCS), 8.8 ±1.68 (Rouleau) and 18.17 ±2.09 (CDIS). alphas were .65 for the CDIS and .479 for the Rouleau. ROC analyses using MoCA scores consistent with any impairment (<26) resulted in a CDIS AOC of .677, with sensitivity of .681 and specificity of .58 at a cut score of 19. The Rouleau AOC was .684, with sensitivity of .542 and specificity of .76 at a cut score of 9. ANOVAs indicated that individuals classified as impaired by the CDIS ((F = 13.095, p<.001) or the Rouleau (F = 22.2, p<.001) rubrics reported significantly more ADL/IADL difficulties than those classified as unimpaired with either rubric. Differences between impaired and unimpaired groups were larger for the CDIS, suggesting this rubric is more sensitive to ADL/IADL deficits.ConclusionBoth rubrics produced generally similar results when compared to the MoCA and adequately identified individuals needing further evaluation given reported functional problems. The CDIS produced more robust differences suggesting that it may be more appropriate for community screening to identify individuals in need of comprehensive cognitive and functional evaluation.
Effects of antiseizure drugs on epileptic activity and synaptic and cognitive dysfunction in transgenic mice expressing A53T human α‐synuclein
Authors: Hwang Kaylin , Vaknalli Rahil , Addo‐Osafo Kwaku , Vicente Mariane Cristine , Peters Samuel T. , Phillips Allyssa , Choquette Jessica M , Bragin Anatol , Lee Michael K , Vossel Keith 
Published: December 2022

AbstractBackgroundAbnormal α‐synuclein (αS) plays an important role in the pathology of Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). New evidence shows network hyperexcitability can accelerate synaptic and cognitive deficits in PDD and DLB. While 90% of epileptiform activity is detected during sleep in Alzheimer’s disease (AD), epileptiform activity during sleep in PDD or DLB is poorly understood. There are currently no known treatments to delay PDD or DLB progression. Although antiseizure drugs (ASDs) have been used to improve memory deficits in AD, this treatment approach has not been investigated in α‐synucleinopathies.MethodsTo explore the effect of ASDs in attenuating αS‐dependent seizure activity, we used transgenic mice expressing the A53T mutant human α‐synuclein (TgA53T) as a model of motor and cognitive decline in PDD and DLB. We have begun screening FDA‐approved ASDs using cortical electroencephalography with electromyography to examine epileptic events 24 hours before and after intraperitoneal injection. The two ASDs exhibiting the strongest efficacy in reducing epileptic activity across sleep‐wake states will be tested for effects on cognitive function and synaptic plasticity following chronic administration. We are also quantifying pathological high frequency network oscillations (HFOs), biomarkers of epileptogenesis.Results3‐4‐month‐old TgA53T mice experienced epileptiform events but had normal long‐term potentiation (LTP) and memory, indicating that epileptic activity onset precedes αS‐induced synaptic and cognitive deficits. Starting at 6 months of age, TgA53T hippocampal slices show the absence of LTP, with reduced c‐fos and calbindin and increased neuropeptide Y indicating alterations in hippocampal inhibitory circuitry. In behavioral testing, TgA53T mice exhibit impairment in fear conditioning, Y‐maze spatial recognition, and Barnes maze spatial learning and memory with age. Preliminary studies indicate lacosamide and brivaracetam as the most effective of ASDs tested in reducing epileptic myoclonus and interictal epileptiform events. We also found more HFOs in TgA53T mice and TgA53T mice with tau ablation.ConclusionSuppression of epileptic activity by ASDs would support ASDs as a novel treatment for reducing or preventing cognitive dysfunction in DLB and PDD. Furthermore, ASD‐induced reversal of synaptic and cognitive deficits would provide evidence that epileptic activity plays a causal role in αS‐dependent pathology.
Plasma glial fibrillary acidic protein as a moderator along the Alzheimer’s disease biomarker cascade
Authors: Saloner Rowan , Asken Breton M. , Gontrum Eva Q. , Chan Brandon , Lago Argentina Lario , Rojas Julio C. , Miller Bruce L. , Rabinovici Gil D. , Casaletto Kaitlin B , Kramer Joel H. 
Published: December 2022

AbstractBackgroundAstrocyte reactivity may contribute to pathogenic relationships between β‐amyloid (A), phosphorylated tau (T), neurodegeneration (N), and cognition (memory). We examined whether severity of astrocyte reactivity, characterized by plasma glial fibrillary acidic protein (GFAP), moderates relationships along the A/T/N and memory cascade in non‐demented adults.MethodPlasma phosphorylated tau181 (P‐tau181) and GFAP concentrations (Quanterix Simoa) were measured in cognitively unimpaired (CU) individuals and patients with mild cognitive impairment (MCI). Analyses were conducted on overlapping sample subsets (aged 52‐92) with florbetapir Aβ‐PET (112 CU [80 Aβ‐, 32 Aβ+; SUVR>1.11], 29 MCI [all Aβ+]), structural MRI (139 CU, 39 MCI), and memory testing (168 CU, 45 MCI). Linear regression tested statistical moderation of plasma GFAP on the association of Aβ‐PET (A) with plasma P‐tau181 (T), and on associations of plasma P‐tau181 with hippocampal volume (N) and composite memory z‐scores (cognition). To probe moderation effects, region of significance analyses identified percentile thresholds along the plasma GFAP distribution at which statistically significant A/T/N and cognition associations emerged. Covariates included age, sex, APOE genotype, education (cognitive analysis), and intracranial volume (MRI analysis).ResultPlasma GFAP significantly moderated the relationship between Aβ‐PET and plasma P‐tau181 (β=0.23, p=.003) and the relationship between plasma P‐tau181 and memory (β=‐0.18, p=.027). Region of significance analyses detected significantly higher plasma P‐tau181 concentrations in Aβ+ (vs. Aβ‐) only above the 17th percentile of plasma GFAP, whereas the significant relationship between higher plasma P‐tau181 and worse memory was only detected above the 73rd percentile of plasma GFAP. Plasma GFAP did not moderate the relationship between plasma P‐tau181 and hippocampal volume (p=.648); however, both plasma P‐tau181 (β=‐0.20, p=.004) and GFAP (β=‐0.16, p=.035) independently related to smaller hippocampal volume.ConclusionAdverse associations along the A/T/N and memory cascade only emerged with increasing plasma GFAP concentrations, with a higher GFAP threshold needed to detect plasma P‐tau181‐related memory associations than Aβ‐related elevations in plasma P‐tau181. These adverse associations were absent at low GFAP levels, suggesting less severe astrocyte reactivity may buffer against AD pathological changes. As a non‐invasive marker of astrocyte reactivity, incorporating plasma GFAP into AD biomarker models may enhance characterization of AD risk and resilience.
Role of Fragile X Mental Retardation protein in Amyloid Beta 1‐42 Induced Translational Suppression
Authors: Lizarazo Simon 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease (AD) is the most common cause of dementia where the accumulation of the peptide Amyloid‐Beta (Aβ) is the main theory linked to the pathogenesis of the disease. Fragile X Mental Retardation Protein (FMRP) is an RNA‐binding protein that functions to suppress global translation. Because Aβ is known to be a toxic peptide capable of inducing the Endoplasmic Reticulum (ER) stress response and because augmented translational suppression is one of the main molecular phenotypes in ER stress response, we ask whether and how FMRP is involved in Aß induced translational suppression.MethodPrimary mouse cortical neuronal cultures from wild type (WT) or Fmr1 KO pups were treated with Aβ (Aβ1–42) during 24 hours. For protein expression identification and quantification we used western blot and ImageJ software respectively. Protein translation was assessed by inhibition with puromycin. Neuronal networking assessment was made with multielectrode array system (MEA).ResultIn this study, we observed that treatments of synthetic Aβ peptides in culture primary mouse cortical neurons induces the expression of FMRP and FMRP‐dependent ER stress response and subsequent translational suppression. Also Aβ induces FMRP‐dependent neuronal hyposynchronicity . We further characterized that two translational regulators, eukaryotic translation initiation factor 2α (eIF2α) and eukaryotic translation elongation factor 2 (eEF2), are involved in Aβ induced translational suppression and are dysregulated in the absence of FMRP. Mechanistically we found that FMRP is responsible for regulating the levels of Protein Phosphatase 2 (PP2A) and Protein Phosphatase 1 (PP1) that differentially modulate the phosphorylation status and thereby activity of eIF2α and eEF2 following treatment of Aβ. Using a pharmacological approach to inhibit PP2A and PP1 with Okadaic Acid, we were able to rescue the impairment of eIF2α and eEF2 as well as the translational suppression and lack of neuronal hyposynchrony in the absence of FMRP.ConclusionThese results suggest a novel function of FMRP in regulating translational suppression and neuronal networking function following Aβ treatment by fine‐tuning two distinct signaling pathways involved in global translation.
Regional blood‐brain barrier breakdown and Alzheimer’s disease pathology in aging
Authors: Becerra Marisa N. , Baker Suzanne L. , Inglis Ben A , Jagust William J. 
Published: December 2022

AbstractBackgroundAlthough blood‐brain barrier disruption (BBBd) is described in aging and AD, its regional characteristics and relationship with AD pathology have not been fully characterized. We aimed to determine whether there are age‐related regional differences in BBBd in cognitively normal adults and if regional BBBd is related to Aβ, tau, and neurodegeneration.MethodBBBd was measured using DCE‐MRI in 9 older adults (OA; 78±6 years, 7M) and 10 young adults (YA; 24±2 years, 7M). The Patlak model was used to generate BBB permeability volume transfer constant (Ktrans) maps in FreeSurfer regions of interest (ROIs). In the OA, PiB‐PET was used to measure global amyloid burden, FTP‐PET to measure tau in medial temporal lobe (MTL) regions, and T1 MRI to measure cortical thickness. We conducted repeated measures ANOVA (group, region, and group x region) with post‐hoc tests to investigate regional differences in Ktrans values between OA/YA and Aβ+/Aβ‐. Linear regressions were used to evaluate the relationships of tau and thickness with Ktrans.ResultsThere was a significant region by age interaction (p< 0.001). OA had greater Ktrans than YA in the entorhinal cortex, parahippocampus, cuneus, fusiform, inferior temporal gyrus (IT), and the lateral occipital cortex (independent sample t‐tests, ps < 0.05; Fig 1). YA had greater Ktrans in the superior and transverse temporal lobe (ps <0.05). In the OA, a trend‐level region by Aβ status interaction (p=0.09) was found for the same ROIs (Fig 2). There were no significant relationships between MTL tau and Ktrans. There was a significant negative relationship between thickness and Ktrans in an averaged ROI consisting of the six regions where OA showed greater Ktrans than YA (p=0.025; Fig 3).ConclusionThese findings show that greater BBBd in OA is relatively specific to the MTL and IT, which are regions affected early in AD. They also suggest that increased BBBd in these regions may be related to amyloid accumulation and neurodegeneration. These findings require extension in larger samples, but implies BBBd as a potentially important event in aging and in the pathophysiology of AD.