bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipoprotein Lipase Regulates Lipid and Lipoprotein Processing in Microglia
Authors: Bruce Kimberley D 
Published: December 2022

AbstractBackgroundLipoprotein Lipase (LPL) is the rate‐limiting enzyme in lipoprotein hydrolysis. In the brain, LPL is predominantly expressed in microglia and is a key feature of phagocytic disease‐associated microglia thought to be protective in AD. Indeed, we have previously shown that microglia lacking LPL show impaired phagocytosis, lipid uptake, and cholesterol efflux (Bruce et al., 2018; Loving et al., 2021). Since ApoE4‐containing brain‐derived lipoproteins increase AD risk, we investigated how LPL regulates microglial lipoprotein processing.MethodHDL‐like lipoproteins were isolated from ApoE2, ApoE3, and ApoE4, expressing astrocytes using HPLC. ApoE‐containing lipoproteins were used as substrates in LPL activity assays and cellular lipoprotein uptake experiments. CRISPR‐Cas9 generated LPL knock‐out (LPL KO) cells were used as genetic controls. To further test the role of LPL in the development of AD we generated a novel microglial‐specific LPL knock‐down mouse (MiLPLKD) on the 5xFAD background (MiLPLKD;5xFAD).ResultApoE4 containing lipoproteins were hydrolyzed less efficiently than ApoE2 and ApoE3 containing lipoproteins by purified LPL in enzymatic activity assays. In addition, ApoE4 containing lipoproteins were endocytosed less efficiently than ApoE2 and ApoE3 containing lipoproteins by LPL expressing microglia. In contrast, LPL‐mediated lipoprotein uptake was inhibited when lipoproteins were pre‐incubated with Aβ. Finally, MiLPLKD;5xFAD mice showed exacerbated cognitive deficits compared to MiLPLKD or 5xFAD controls.ConclusionWhile LPL mediates microglial‐lipoprotein uptake, both lipoprotein hydrolysis and endocytosis is inhibited in the presence of ApoE4. This suggests that LPL‐mediated lipoprotein uptake is a critical homeostatic mechanism in the brain that is dysregulated in the presence of ApoE4, contributing to AD progression.
Presenilin 2 Knockout Mice are More Sensitive to Acute Valproic Acid in the 6 Hz Model of Focal Seizures
Authors: Lehmann Leanne M , Barker‐Haliski Melissa 
Published: December 2022

AbstractBackgroundPatients with Alzheimer’s disease (AD) experience undetected focal seizures, which could worsen overall disease burden (e.g., accelerate cognitive decline and worsen neuropsychiatric comorbidities). Genetic variants in presenilin 2 (PSEN2) are associated with early‐onset AD and result in a loss of normal PSEN2 function, which forms the catalytic component of the g‐secretase enzyme. These patients also experience seizures (Jayadev et al, Brain 2010). Nonetheless, seizures in PSEN2 variant mouse models of AD are significantly understudied (Lehmann et al, Neurochem Res 2021); most prior preclinical work assessing seizure susceptibility and antiseizure drug (ASD) efficacy has been conducted in amyloid precursor protein‐overexpressing models. There are over 30 approved ASDs that may be effective in controlling seizures in AD. However, ASD efficacy and tolerability is not routinely assessed in aged rodent seizure models, nor in models with AD‐associated genotypes. This project thus aimed to establish the dose‐dependent anticonvulsant efficacy of ASDs in the mouse 6 Hz model of focal seizures evoked in PSEN2 knockout (KO) mice.MethodMale and female PSEN2 KO and WT C57Bl/6 mice aged 3‐4 months were used to determine the median effective dose (ED50) of prototype ASDs (including valproic acid and carbamazepine). ASDs were acutely administered to assess dose‐related seizure control in the 6 Hz test based on our published methods (Koneval et al, Epilepsia 2020).ResultThe ED50 of valproic acid (VPA) in male PSEN2 KO mice was 62.7 mg/kg [48.6‐90.8]; significantly lower than the VPA ED50 for age‐matched male WT mice (158 mg/kg [108‐242]). In females, the VPA ED50 for PSEN2 KO mice was 93.3 mg/kg [39‐159], while in age‐matched WT female mice it was 163 mg/kg [120‐235]. Notably, the ED50 of carbamazepine (CBZ) in male PSEN2 KO mice (14.5 mg/kg [2.23 ‐ 23.6]) was not substantially different from WT mice.ConclusionPSEN2 KO mice may be more sensitive to acute administration of VPA than WT mice in the 6 Hz focal seizures model, but this sensitivity is not universal to all ASDs. This study demonstrates that loss of normal PSEN2 function may selectively increase the potency of clinically‐approved ASDs in this preclinical model of focal seizures.
Amyloid induced neuronal hyperexcitability triggers progressive epilepsy
Authors: Tanila Heikki 
Published: December 2022

AbstractBackgroundUnprovoked seizures are more common in Alzheimer (AD) patients than in general population and subclinical epileptiform activity has been reported in 20‐40% of early‐stage AD patients. Similarly, spontaneous seizures and epileptiform spiking have been reported in all commonly used amyloid plaque producing APP transgenic mouse lines. Furthermore, epileptiform spiking in both AD patients and APP transgenic mice occurs almost exclusive during sleep. These observations speak for common underlying mechanism across species.MethodWith the help of in vivo multichannel and multi‐site local field potential recordings and post‐mortem immunohistochemistry in APP/PS1 mice we have aimed to find answers to three keys questions about AD‐related epilepsy. (1) Is there a focal onset of epileptiform activity in the brain? (2) How does the hyperexcitability relate to amyloid plaque formation? (3) Is the problem primarily of enhanced excitation or attenuate inhibition?ResultIn most cases we have identified hippocampus (both CA1 and dentate gyrus) as the focus for epileptiform activity, although some spikes have cortical origin. Neuronal hyperactivity and epilepsy related sudden deaths tend to peak around the time when first amyloid plaques are formed. On the other hand, intracellular accumulation of full‐length APP or its C‐terminal fragment does not seem to correlate with increased excitability. In line with reported increased glutamate release in the hippocampus of APP/PS1 mice, we found increased vGlut immunopositive terminal around amyloid plaques. Studies on paralbumin‐positive interneurons are ongoing.ConclusionAmyloid plaque formation in the hippocampus is at least one of the triggers for AD‐related epileptiform activity.
Sensory stimulation improves daily functions in Alzheimer’s disease
Authors: Cimenser Aylin , Hempel Evan , Konisky Alexandra , Vaughan Brent , Megerian Jonathan Thomas , Malchano Zach , Hajos Mihaly 
Published: December 2022

AbstractBackgroundAbnormal neuronal function in Alzheimer’s disease (AD) is characterized by unbalanced neuronal excitatory‐inhibitory tone, distorted neuronal synchrony, and network oscillations, presumably contributing to the pathogenesis of the disease and accelerating disease progression. The probability that abnormal neuronal activity directly contributes to the pathogenesis of the disease has been recently proposed. It has been demonstrated that induction of synchronized gamma oscillation of neuronal networks by sensory stimulation reverses AD‐related pathological markers in transgenic mice carrying AD‐related human pathological genes. The current study evaluated whether non‐invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for patients in AD spectrum.MethodThe data studied here is from Overture clinical trial (NCT03556280). The study included a treatment group, where participants received daily, 1‐hour, 40Hz gamma visual and auditory stimulation for 6‐months at home, and a placebo group. To assess the treatment efficacy on daily functional abilities, the Alzheimer’s Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL) scale was used. Assessments were made at baseline and every four weeks throughout the study. ADCS‐ADL consists of 23‐items where each item aims to assess different functional abilities. The change in ADCS‐ADL as well as change in each individual item’s score between the treatment group (n = 33) and the placebo group (n‐ = 19) were compared using a mixed model for repeated measures (MMRM).ResultWe observed that treatment group participants were able to maintain their functional abilities while placebo group participants showed a decline as assessed by ADCS‐ADL, p<0.001. Within the instrumental ADCS‐ADL individual items, the most significant differences between the two groups, all favoring treatment group, were observed in: (1) Attentive participation in conversations, p<0.001, and (2) Finding personal belongings, p<0.043.ConclusionOur results suggest that daily, 1‐hour 40Hz gamma sensory stimulation may help prevent functional decline in patients with AD spectrum disorder. Preventing functional loss would help both patients and caregivers. Furthermore, it may reduce the need for institutionalization and reduce healthcare costs. Larger studies are planned to confirm these initial findings on the benefits of gamma sensory stimulation on function.
Digital Pathology Investigation of SERPINA5‐Tau Protein Interaction in Alzheimer’s Disease and Primary Tauopathies
Authors: Sirmans Tiffany N. Hicks , Kouri Naomi , Tamvaka Nicole , Labuzan Sydney A , Matchett Billie J , Lincoln Sarah J. , Hinkle Kelly M , Moloney Christina M. , Peng Zhongwei , Carter Rickey E , Ross Owen A. , Ertekin‐Taner Nilufer , Duara Ranjan , Graff‐Radford Neill R. , Dickson Dennis W. , Murray Melissa E. 
Published: December 2022

AbstractBackgroundWe recently discovered a novel tau binding partner, SERPINA5, to be upregulated in Alzheimer’s disease (AD) and co‐localize with corticolimbic tau distribution. As tau pathology is also observed in primary tauopathies, we hypothesized that SERPINA5 burden would mirror tau burden in these diseases. Thus, we sought to define the relationship between SERPINA5 and tau in primary tauopathies and compare this relationship to AD.MethodImmunohistochemistry was performed on the hippocampus or cingulate in 4 groups (n=6 per disease group): 1) AD, 2) 3R+4R primary age‐related tauopathy, 3) 4R tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grains disease), and 4) 3R tauopathy (Pick’s disease). Burden analyses for SERPINA5 and a phospho‐tau marker (AT8) were performed on digitized whole slide images.ResultVisual interpretation of SERPINA5 immunostaining identified both neuronal and glial inclusions that are commonly AT8‐positive in primary tauopathies. There were exceptions to this pattern such as SERPINA5‐positive Pick bodies being rarely observed. However, some pathologic structures, like ballooned neurons, were preferentially stained by SERPINA5. Quantitative analyses confirmed this observation with AT8 and SERPINA5 burden correlating in both the cingulate (R2=0.47, p<0.0001, Figure 1a) and hippocampus (R2=0.74, p<0.0001, Figure 1d). Nonparametric rank sum tests revealed majority of the primary tauopathies had less AT8 and SERPINA5 burden compared to AD in both the cingulate and hippocampus (Figure1b‐c, e‐f; Table 1).ConclusionSERPINA5 immunostaining patterns in primary tauopathies reflect tau immunostaining patterns. Our data suggests the SERPINA5‐tau interaction may not be specific for AD, which may implicate the role of SERPINA5 more broadly across tauopathies.
Anterior chamber enhancement – a window into the orbital glymphatic system and beyond?
Authors: Deike‐Hoffmann Katerina , von Lampe Paula , Eerikaeinen Maija , Ting Saskia , Schlüter Sabrina , Schlemmer Heinz‐Peter , Bechrakis Nikolaos , Forsting Michael , Radbruch Alexander 
Published: December 2022

AbstractBackgroundRecently, an orbital glymphatic system (GS) was described, that serves retinal homeostasis and clearance. In accordance to the brain GS, the orbital GS is supposed to be altered in a variety of disease, first and foremost Alzheimer's Disease (AD). Disturbances of the orbtial GS where suggested to serve as early (imaging) biomarker. Therefore it is highly desirable to visualize orbital GS function in vivo. This study investigated intravenously injected Gadolinium‐based contrast agent (GBCA) to visualize the orbital GS. We used a retrospective patient cohort of children suffering from retinoblastoma (RB) who are supposed to show altered orbital GS function to test the validity of this method.MethodThis IRB approved retrospective single‐center study encompassed 539 orbital MRIs performed with an orbital coil and with the children in a state of general anesthesia.Differences of signal intensity ratios of the AC to the lens (∆SIRs) were determined between native and GBCA‐enhanced T1‐weighted images. Subsequently, ∆SIRs were correlated with histopathologic tumor features such as infiltration of the ON, choroid, ciliary body, sclera and AC.Result∆SIR of the RB eye was an independent, significant predictor for ON infiltration in multivariate analysis with adjustment for tumor size (p < 0.05) and increased with infiltration level (compare fig. 1A+B). ∆SIR was not predictive for any other assessed histopathologic tumor feature.ConclusionGBCA enhancement of the AC predicts ON infiltration by RB. This might be caused by impairment of the orbital GS, which is supposed to clear toxic metabolites from the retina to the postlaminar ON (compare fig. 2). In RB with ON infiltration, this efflux path might be inhibited, which is supposed to result in disturbed retinal homeostasis, release of vascular endothelial growth factor and iris neovascularization with increased penetration of GBCA into the AC (compare fig. 3). We conclude, that GBCA‐enhanced MRI might enable visualization of (orbital) GS function in vivo and suggest assessment of this imaging approach in patients with neurodegenerative diseases.
Change in Plasma ATN Biomarkers Over a 12‐Week Physical Activity Intervention Among Older African Americans: Program for African American Cognition and Exercise (PAACE)
Authors: Carmichael Owen T. , Gwizdala Kathryn L. , Brouillette Robert , Beyl Robbie , Johnson William , Hebert Callie , Carter Leah , Harris Melissa , Newton Robert L 
Published: December 2022

AbstractBackgroundPlasma markers of amyloid, tau, and neurodegeneration (ATN) are promising as correlates of AD biological and clinical features, but data from older African Americans, and data on change during non‐pharmacological interventions, is limited.MethodThe Program for African American Cognition and Exercise (PAACE) randomized older cognitively normal African American adults into a 12‐week successful aging group (SAG) to attend educational sessions or a 12‐week physical activity group (PAG) to complete supervised and in‐home physical activity. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and cardiometabolic risks were assessed pre‐ and post‐intervention. The Quanterix Simoa® Neuro 4‐Plex E and pTau‐181 Advantage Kits were used to measure plasma concentrations of amyloid beta (ABeta) 1‐40 and 1‐42, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau protein phosphorylated at threonine 181 (pTau‐181). Linear mixed effects regression models assessed modifiers of change in plasma and RBANS measures.ResultA set of 54 PAACE completers aged 69.3 +/‐ 3.4 years (40 female, 14 male) provided non‐outlier measurements. ABeta 1‐40 decreased (p=.027), and RBANS global cognition, visuospatial, and delayed memory scores increased, over the intervention (maximum p value: .040). Plasma ATN biomarkers did not differ between SAG and PAG at baseline, but SAG did have greater declines in pTau‐181 than PAG did (p=.003, Figures 1‐2), and women had greater declines in pTau‐181 than men did (p= .045, Figure 3). Greater age was associated with greater ABeta 1‐40, ABeta 1‐42, GFAP, and NFL (maximum p= .008). Greater diastolic blood pressure was associated with lesser NFL (p= .021) and ABeta 1‐40 (p= .041). Greater GFAP, NfL, and pTau‐181, suggestive of greater burden of tau and neurodegeneration, were associated with lesser RBANS language score (maximum p= 0495). Greater pTau‐181 was associated with lesser RBANS immediate memory score (p= .035). Plasma ATN markers did not modify pre‐to‐post‐intervention change in any RBANS summary score (minimum p=.10).ConclusionAmong cognitively normal older African Americans, change in plasma ATN biomarkers over the course of a nonpharmacological intervention differed by study group and gender. The markers differed by cardiometabolic risks and associated with cognitive function in an intuitive fashion.
Distinct signatures of white matter damage in cerebral small vessel disease and Alzheimer’s disease: a fixel‐based analysis study
Authors: Dewenter Anna , Gesierich Benno , Hager Paul , Biel Davina , Ewers Michael , Franzmeier Nicolai , Duering Marco 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) and cerebral small vessel disease (SVD) are the two main causes of age‐related cognitive decline and frequently co‐exist in memory clinic patients. White matter diffusion alterations have been described as key features of both diseases with different spatial patterns in AD and SVD. Biomarkers that capture and disentangle the effects of each disease on white matter integrity are of great need but are still lacking. Advanced diffusion MRI‐based techniques on the fixel level (fiber population within a voxel) yield promise, since one can derive measures of both fiber density and fiber bundle cross‐section (Dhollander et al., Neuroimage, 2021). In this multimodal imaging study, we assessed the ability of these fixel metrics to detect disease‐specific signatures of white matter fiber tract damage yielding the path towards personalized medicine.MethodWe included genetically defined SVD (n=73) and the full continuum of biomarker‐characterized AD from ADNI (n=34 Aβ–T–; n=19 Aβ+T–, n=18 Aβ+T+). Using multi‐shell diffusion MRI, we assessed the fiber density and fiber bundle cross‐section of six well‐established white matter fiber tracts previously shown to be damaged or related to cognitive decline in AD and SVD (see Figure 1). Using simple linear regression analyses and while controlling for intracranial volume, we determined associations between tract‐specific fixel metrics and imaging markers of SVD (white matter hyperintensity volume, lacune and microbleed count) and AD (global amyloid‐ and tau‐PET SUVR) as well as age and brain volume.ResultFiber density of all fiber tracts was strongly associated with white matter hyperintensity volume in SVD (e.g. inferior fronto‐occipital fasciculus, R2adj=73%). In contrast, fiber bundle cross‐section was highly associated with cerebral atrophy in the AD sample (e.g. corpus callosum, R2adj=36%). Of note, both fiber density and fiber bundle cross‐section were only weakly associated with amyloid‐ and tau‐PET (e.g. fiber density of uncinate fasciculus ∼ amyloid‐PET, R2adj=11%; fiber bundle cross‐section of inferior longitudinal fasciculus ∼ tau‐PET SUVR, R2adj =5%).ConclusionFiber density captures the effects of SVD on white matter integrity whereas fiber bundle cross‐section indicates tract‐specific neurodegeneration in AD. Fixel‐based analysis allows to assess disease‐specific effects of SVD and AD on white matter fiber tracts.
Brain Derived Biologically Relevant Tau Oligomers
Authors: Kayed Rakez 
Published: December 2022

AbstractBackgroundNeurodegenerative Tauopathies, including Alzheimer’s disease (AD), are characterized by the appearance of extracellular lesions composed of aggregated and post‐translationally modified tau proteins. The resulting tau pathology is an established marker for differential disease diagnosis and staging, a surrogate marker for neurodegeneration, a potential vector for disease propagation, and a source of toxicity in biological models. In comparison to the well‐established methods for isolation/preparation and biochemical and structural characterization of stable tau filaments from tauopathy brain, the characterization of smaller and much dynamic oligomeric tau aggregates has not been investigated to the same degree. As a result, tau oligomers that may associate most closely with disease propagation and toxicity as suggested by a large body of research, are not fully established.MethodHerein, we leverage our well‐optimized brain‐derived tau oligomers (BDTOs) from well‐vetted human tauopathy cases of AD, progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB). In addition to our rigorous biochemical characterization of the BDTOs by immunological probing, and structural characterization by proteolysis and microscopic analyses, we have optimized Fluorescent Amyloid Multi Emission Spectra (FLAMES) microscopy for cataloging and comparing tau conformational variants across a wide range of samples, from brain tissue sections and BDTOs to in vitro aggregated tau assemblies. For selective immunodetection of the BDTOs, we have used our novel four fully sequenced and epitope mapped Tau Oligomer Monoclonal Antibodies (TOMAs), which recognize non‐continuous sequences on tau. Furthermore, the bioactivity of the BDTOs was assessed by evaluating their seeding propensity in biosensor cells and primary cortical neurons from tauopathy mice and their effects on synaptic function by electrophysiological studies.ResultWe observed that the BDTOs differed in their immunological properties, morphology, and sensibility/stability to proteolysis. The BDTOs were distinguished based on FLAMES spectral signature. Distinct seeding propensity and impairment of long‐term potentiation (LTP) indicated their differences in bioactivity as well.ConclusionOur thorough investigation/characterization of biologically active disease‐relevant tau oligomers will provide new opportunities to diagnose and evaluate therapeutics beyond the current capabilities for AD and related tauopathies by developing specific tau aggregation inhibitors and/or diagnostic probes for pathological tau protein.
The rationale behind the NIA‐AA research framework definition of Alzheimer's disease
Authors: Jack Clifford R. 
Published: December 2022

AbstractBackgroundThe NIA‐AA research framework group and the IWG both agree that abnormal AD biomarkers are necessary for the diagnosis of AD; however, the groups disagree on the appropriate definition of Alzheimer’s disease. The NIA‐AA framework argues that a CU A+T+ individual has AD pathology and therefore has the disease. The IWG argues that such an individual should be labeled “at risk for AD” because both abnormal biomarkers and clinically significant impairment are required for an AD diagnosis.MethodThe major IWG argument against a biological‐only definition of AD is that some CU A+T+ individuals will die of other causes without experiencing overt symptoms (MCI or dementia) in their lifetime. However, the same statement can be made about any other disease in medicine. The question therefore must be how often will CU A+T+ individuals die without experiencing dementia.ResultMany studies have examined rates of cognitive decline in CU A+ relative to CU A‐ (fewer studies in CU A+T+ vs CU A‐T‐). Studies have examined the risk of incident MCI/dementia in CU A+ relative to CU A‐ (fewer in CU A+T+ vs CU A‐T‐). Relative risk indicates likelihood of an outcome in a particular risk group relative to a reference group; it does not indicate the likelihood in percentage terms that an individual will experience an outcome in their lifetime. It is lifetime risk (i.e., absolute risk) that is needed to address the current controversy and to our knowledge only 2 published studies have estimated lifetime risk associated with AD biomarkers. A recent Mayo Clinic Study of Aging analysis examined lifetime risk of dementia associated with varying levels of amyloid PET, APOE and sex. Among APOE ε4 carriers with high amyloid PET SUVR, remaining lifetime risk of dementia at age 75 years was 76% for women and 64% for men. Lifetime risk of CU A+T+ remains to be determined, however.ConclusionThe major discordance between the NIA‐AA framework and the IWG (the definition of AD) points to the question, how risky is the CU A+T+ state? Accurate estimates of lifetime risk from population‐based studies are needed to address this question.