bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered cerebrovascular reactivity along functional networks in older adults with long COVID
Authors: Pommy Jessica , Cohen Alexander D , Patel Milan , Umfleet Laura Glass , Franczak Malgorzata , Brett Benjamin L , Obarski Shawn , Agarwal Mohit , Ristow Kelly , Swanson Sara J , Wang Yang 
Published: December 2023

AbstractBackgroundCerebrovascular reactivity (CVR), an indicator of neurovascular function associated with cognitive decline, relies on vascular and inflammatory processes, making it a potential mechanism of interest driving neurological changes in long COVID among older adults. Given the variability in symptoms associated with long COVID, distribution corrected z‐scores (DisCo‐Z), a subject‐specific abnormalities (SSA) approach more suited for heterogenous conditions, was employed to examine CVR and long COVID in older adults. Relationships between CVR, post‐COVID subjective cognitive decline (pcSCD), and cognitive function were examined.Methods15 older adults with long COVID (M age = 63.9, 6 males) and 24 healthy older adults (M age = 66.7, 6 males) performed a breath‐holding task while in the MR scanner to examine CVR. DisCo‐Z was used to examine the presence and size of extreme clusters of increased or decreased CVR (>100 voxels) within the 7 Yeo functional networks. Non‐parametric tests were used to examine group differences in presence and mean size of extreme clusters. Finally, relationships between: 1) extent of pcSCD and extreme cluster values in long COVID, and 2) cognitive testing scores and global “burden” (cluster size mean and sum) were examined.ResultsGroups did not differ significantly on gender (p = .323) or age (p = .324). Greater incidence of positive extreme clusters within Ventral Attention (p = .028) and Limbic (p = .049) networks were observed in long COVID (with minimal incidences of negative extreme clusters across networks). Group differences were observed for mean cluster size in the Ventral Attention network (p = .016), as well. Extent of pcSCD was positively correlated with DisCo‐Z values for the Ventral Attention network (p = .021) with a trending level of significance for the Limbic network (p = 0.053). Finally, within the full sample, global CVR burden was negatively correlated with memory test scores (p = 0.014).ConclusionsUsing the SSA approach, group differences in CVR were observed in older adults experiencing long COVID. In particular, differences were observed within functional networks thought to drive attention, executive function, and emotional control, which was correlated with pcSCD. Finally, global CVR burden was negatively correlated with memory. These findings, though preliminary, suggest CVR may represent a potential neurobiological mechanism driving pcSCD in older adults.
P301L‐Tau Expression Induces Skeletal Muscle Abnormalities in Mouse Model of Tauopathy
Authors: Alava Bryan , Esser Karyn , Abisambra Jose F. F 
Published: December 2023

AbstractBackgroundPatients suffering from Alzheimer’s disease (AD) and related tauopathies often report signs of muscle weakness. The pathological accumulation of insoluble tau that forms neurofibrillary tangles (NFTs) is a hallmark of AD, yet it is unclear whether pathological tau impacts skeletal muscle. Proper muscle function is necessary for movement and consequently impacts quality of life in tauopathy patients, while concurrently contributing to the physiological maintenance of whole‐body endocrine and metabolic homeostasis. Skeletal muscle crosstalks with other organ systems; therefore, disruption of skeletal muscle health impacts whole‐body processes, such as the formation of pathological tau. The objective of this study was to determine the links between tauopathy and muscle function.MethodI performed intracerebroventricular injections with adeno‐associated viral (AAV) vector encoding P301L human tau (N = 4 females, 7 males) or a control plasmid (empty or a yellow fluorescent protein construct) (N = 5 females, 6 males). At 3 months, I measured grip strength. I harvested the brain, soleus, and tibialis anterior (TA) muscles at 15 months, and measured muscle mechanics concurrently in the soleus and extensor digitorum longus (EDL) muscles. I biochemically detected soluble tau and visualized TA structure immunohistochemically.ResultsGrip strength was reduced at 3 months in the P301L tau‐expressing mice of both sexes. The intrinsic force production of the soleus, but not the EDL, was reduced in P301L tau‐expressing males at 15 months. At this same time point, soluble tau accumulated in the cortex but not the soleus. Aggregation of nuclei were found histologically in the TA of P301L tau expressing mice but not in controls.ConclusionChanges in grip strength preceded insoluble tau accumulation and cognitive decline typical of this model. Reductions in the soleus force production indicate that P301L tau overexpression in the brain impacts intrinsic muscle strength, and occurs independently of innervation. The nuclear clumps detected in the TA of P301L tau‐expressing mice suggest that AAV‐P301L‐tau injections in the brain promote an inflammatory response in muscle. Together these data suggest that pathological tau species that are expressed in the brain reach peripheral tissues and exert deleterious consequences such as skeletal muscle abnormalities.
Plasma Neurofilament Light and Markers of Sensorimotor Function in a Predominantly Hispanic Population of Older Adults in San Antonio, Texas
Authors: Kautz Tiffany F , Velarde Angel G. , Francis Lily , Bernal Rebecca , Goss Monica , LaRoche Ashley , Katragadda Haritha V. , Vasquez Erin Livia , Mathews Julia J , Muhammad Jazmyn A , Saklad Jared , Kivisäkk Pia , Singh Herpreet , Greenberg Steven M. , Alliey‐Rodriguez Ney , Maestre Gladys E. , Gonzales Mitzi M. , Jacob Mini E , Seshadri Sudha , Satizabal Claudia L. 
Published: December 2023

AbstractBackgroundSensorimotor and blood‐based biomarkers are promising dementia biomarkers with high accessibility and limited invasiveness. Although sensorimotor changes appear with aging, more severe changes may precede cognitive decline, dementia, and other neurological diseases. Additionally, blood‐based neurofilament light (NfL), a broad marker of neuroaxonal injury, is commonly elevated in many types of neurological disease. Prior studies have suggested that increased blood levels of NfL in conjunction with sensorimotor decline may allow for earlier neurological disease diagnosis and/or prediction of disease severity, but little is known about the correlation of these markers in the general population. We examined the association between NfL and sensorimotor markers in a predominantly Hispanic population in San Antonio, Texas.MethodOur sample included older adults from our San Antonio MarkVCID and South Texas Alzheimer’s Disease Research Center (ADRC) cohorts (n = 152, mean age 71.2±7.63, 60.4% women, 79.5% Hispanic) with available plasma NfL, olfaction (B‐SIT age‐adjusted percentile), grip strength, and touch (monofilament) data (Table 1). NfL concentrations were log‐transformed to achieve a normal distribution. We used linear or logistic regression models, as appropriate, to assess the association between NfL and sensorimotor outcomes, adjusting for age, sex, race, ethnicity, and cognitive diagnosis.ResultHigher plasma NfL was significantly associated with decreased olfaction score percentiles (Beta [95% Confidence Interval], β = ‐8.79; [95% CI ‐16.89; ‐0.12], p = 0.05), grip strength in either hand (left: β = ‐3.62; [95% CI ‐5.51; ‐1.74], p = 0.0002; right: β = ‐2.99; [95% CI ‐5.01; ‐1.03], p = 0.003), and impaired touch perception (Odds Ratio [95% CI], OR = 2.56; [95% CI 1.01; 6.48]; p = 0.05), independent of the potential confounders listed above.ConclusionThese results highlight the association of plasma NfL with several markers of sensorimotor function, which may reflect central and peripheral neuroaxonal injury. Additional studies are needed in larger community samples to confirm these findings and explore the potential of NfL as a marker of functional decline in longitudinal studies. We plan to continue collecting these markers, as well as gait and balance, longitudinally to gain a better understanding of the link between neurodegeneration, sensorimotor markers, and neurological disease trajectory in our unique South Texas population.
Circadian genes in wake‐promoting neurons have a different pattern of expression in Alzheimer’s Disease, Progressive Supranuclear Palsy, and Healthy Controls
Authors: Pereira Felipe Luiz , Satpati Abhijit , Raju Anya , Soloviev Alexander , Mladinov Mihovil , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Ehrenberg Alexander J. , Neylan Thomas C. , Grinberg Lea T. 
Published: December 2023

AbstractBackgroundIndividuals with neurodegenerative disorders often experience sleep disturbances before showing any other symptoms. Our recent studies found a link between tau‐driven degeneration of wake‐promoting neurons (WPN) and sleep/wake dysfunction in Alzheimer’s disease (AD), which is a shift from the previously held beta‐amyloid centric models for sleep dysfunction. The circadian system regulates WPN, but little is known about the pattern of circadian dysregulation in WPN in AD and other tauopathies. Methodological limitation such as undefined borders and the small size of WPN nuclei makes it challenging to perform such studies. We performed gene expression analysis using the nCounter human neuropathology panel and circadian genes custom code set (Nanostring, USA) to map these changes and inform customized therapies.MethodRNA was isolated from wake‐promoting areas: locus coeruleus (LC), lateral hypothalamic area (LHA), and tuberomammillary nucleus (TMN) dissected from Formalin‐Fixed Paraffin‐Embedded (FFPE) postmortem brain tissue of 6 AD, 7 progressive supranuclear palsy (PSP), and 5 healthy controls (HC) cases with similar ages at death. RNA expression levels were determined using bead‐based hybridization technology and differential expression analysis was conducted using DESeq2 with Wald statistical test and adding sex as a confounding variable.ResultWe identified differentially expressed circadian genes in WPN across disease conditions vs. HC (Figure 1) and between AD and PSP. Clock/Npas2 genes only have differential expression in PSP (although in different directions in LHA vs. TMN). PER gene families had changes in AD and PSP, but only in LHA and TMN.ConclusionExpression of circadian genes is dysregulated in WPN in AD and PSP, but the pattern is considerably different, with some gene families showing opposite directions of regional expression even in the same disease (i.e Clock/Npas2 and Cry). Interestingly, circadian dysregulation in hypothalamic neurons is more significant than in LC, possibly reflecting direct connections between the suprachiasmatic nucleus, the circadian clock, and TMN and LHA. This study supports the utility of fixed‐tissue‐based RNA expression analysis to unveil the molecular basis of sleep dysfunction in neurodegenerative diseases, even considering the complex neuroanatomy of the sleep‐controlling regions. Validation of these findings using multiplex immunohistochemistry and clinicopathological correlations are ongoing.
CSF‐plasma albumin ratio differs by sex in community dwelling older adults
Authors: Yates Alexis , Zhang Panpan , Liu Dandan , Pechman Kimberly R. , Houston Michelle L , Davis L. Taylor , Landman Bennett A. , Gifford Katherine A. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2023

AbstractBackgroundBlood‐brain barrier (BBB) permeability is associated with Alzheimer’s disease (AD) and neurodegeneration. Cerebrospinal fluid (CSF)/plasma albumin ratio (QAlb) is a biomarker commonly used to approximate BBB and blood‐CSF barrier (BCSFB) integrity. While sex‐based differences in AD risk are well‐established, limited work has evaluated these differences with QAlb and neurodegeneration and neuropsychological outcomes. Here, we examine if sex modifies the association of QAlb with neuropsychological and structural neuroimaging markers of neurodegeneration in community‐dwelling older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, 72±7 years, 33% female) completed a fasting blood draw, lumbar puncture, neuropsychological assessment, and multimodal 3T brain magnetic resonance imaging (MRI) to capture grey matter volumes and white matter hyperintensities (WMHs). Ordinary least squares regressions cross‐sectionally related sex to QAlb. Follow‐up models tested a sex x QAlb
interaction with neuropsychological and MRI outcomes. Models adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile score (minus age), apolipoprotein (APOE)‐e4 status, and (for MRI outcomes) intracranial volume.ResultFemale sex was associated with lower QAlb (p<0.001). However, sex did not interact with QAlb on any neuropsychological (p‐values>0.7) or neuroimaging outcomes (p‐values>0.2). Models stratified by sex were also null for neuropsychological (p‐values>0.93) and neuroimaging outcomes (p‐values>0.11).ConclusionElevated QAlb is believed to reflect disrupted brain‐barrier integrity such that blood‐based albumin (which lacks an active transport mechanism across the BBB) can enter the brain parenchyma and travel to the CSF. We found that female sex is associated with lower QAlb levels but does not interact with early cognitive or neuroimaging markers of AD‐associated neurodegeneration. The strong association between female sex and higher brain‐barrier integrity highlights the importance of considering sex differences when applying QAlb in clinical and research settings.
Funding: R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082
Amyloid and tau deposition is associated with performance on tests of auditory processing in the brain
Authors: Stevenson Alyssa , Rahmouni Nesrine , Leigh Samantha , Stevenson Jenna , Rosa‐Neto Pedro , Niemczak Chris , Buckey Jay 
Published: December 2023

AbstractBackgroundAlzheimer’s disease pathophysiology may affect sound processing (central auditory function) in the brain. This study aims to investigate the link between tests of central auditory function, such as dichotic digits, and brain pathology in older adults at high risk for developing dementia.Method28 individuals (13 cognitively unimpaired (CU) and 15 mild cognitively impaired (MCI)) were enrolled (Table 1). Amyloid deposition was assessed with [18F] AZD4694 PET and tau accumulation was assessed with [18F]MK6240 PET. Standard uptake value ratios (SUVR) were determined using the cerebellar and the inferior cerebellar cortex as reference region for amyloid and tau PET, respectively. Hearing assessments were conducted using a custom audiological testing system from Creare LLC. Voxel‐based regression models evaluated the association between dichotic digit scores and amyloid and tau deposition as assessed by PET, adjusting for Pure Tone Average (PTA) and a control condition for speech in noise (Triple digits score). Random field theory (RFT) was used to correct for multiple comparisons.ResultIn the voxel‐wise analysis, negative associations between dichotic digits scores and amyloid‐PET were found in the temporal, occipital and parietal areas. Negative associations between dichotic digits scores and tau‐PET were present in the temporal area, with higher t‐values in the primary and secondary somatosensory cortices (Figure 1, panel A). Negative correlations were found between dichotic digits scores and both amyloid (p<0.001) and tau (p<0.05) SUVRs (Figure 1, panel B). In addition, dichotic digits scores were significantly lower in MCI individuals (p<0.001) (Figure 1, panel C).ConclusionThis study is the first to assess associations between central auditory hearing in CU and MCI individuals using PET biomarkers. These findings highlight the link between central auditory deficits and AD hallmarks in auditory processing‐related brain regions. This suggests a potential decreased capacity for interhemispheric transfer in mildly cognitively impaired individuals.
Tau deposition patterns within the medial temporal lobe follow the connectivity of the entorhinal cortex – a combined post‐mortem and 7T fMRI study
Authors: Franzmeier Nicolai , Berron David , Binette Alexa Pichet , Grande Xenia , Hansson Oskar , Ossenkoppele Rik 
Published: December 2023

AbstractBackgroundIn aging, tau pathology develops in the medial temporal lobe (MTL), but spreads extensively to the cortex in the presence of amyloid‐beta, driving neurodegeneration and Alzheimer’s disease (AD) dementia development. This suggests that earliest age‐related MTL tau is a pre‐requisite for cortical tau spreading and the development of AD. Using tau‐PET in AD, we found previously that functional connectivity routes the cortical expansion of tau, supporting the concept of trans‐neuronal tau spreading. However, it is unclear whether MTL tau accumulation follows within‐MTL connections, in particular those of the entorhinal (EC) and transentorhinal cortex (A35), i.e. the earliest sites of tau accumulation. To address this, we combined post‐mortem histopathological MTL tau assessments with high‐resolution 7T functional MRI to determine MTL subregional connectivity.MethodsWe included 3D post‐mortem quantitative histopathological tau assessments of 14 MTL subregions (Fig.1A) in 18 participants with overall low AD neuropathological change to capture earliest tau (Fig.1B), and 7T resting‐state fMRI from young and healthy controls (n = 29) to characterize MTL functional connectivity. Using post‐mortem data, we assessed the covariance of AT8‐stained tau among MTL subregions (Fig.1C) and assessed the correlation with functional connectivity among the same regions (Fig.1D). Further, we determined seed‐based connectivity to determine which MTL subregions connectivity pattern was the best predictor of MTL‐wide tau patterns.ResultsPost‐mortem tau levels were highest in the amygdala, followed by A35 and the EC (Fig.2A). As hypothesized, we found an association between MTL connectivity and covariance in MTL tau (r = 0.42, p<0.001, Fig.2B), where closely connected regions showed correlated tau. When assessing seed‐based connectivity as a predictor of MTL tau patterns, EC connectivity was the best predictor for MTL tau deposition patterns (Fig.2C).ConclusionsClosely connected MTL subregions show correlated histopathologically‐assessed tau load, suggesting connectivity to route earliest within MTL tau spreading. Despite highest tau in the amygdala, EC connectivity was the best predictor of MTL tau patterns, suggesting that the EC is a key source for within MTL tau spreading. This can be critical to assess EC connectivity as a potential treatment target to prevent cortical tau spreading and thus neurodegeneration and cognitive decline in AD.
MRI Markers for Detecting Accelerated Alzheimer’s Disease after Neurotrauma
Authors: Hua Ning , Minaeva Olga , Parsons Douglas , Moncaster Juliet A , Goldstein Lee E 
Published: December 2023

AbstractBackgroundA history of traumatic brain injury (TBI) is linked to an earlier onset of Alzheimer’s disease (AD) (Nemetz et al., 1999). Evidence showed that the more severe the injury, the greater risk of developing AD (Johnson et al.,2010). However, systematic evaluation of in vivo MRI markers in the monitoring of AD progression after trauma is lacking. Here, we investigated the performance of various MRI markers in tracking AD progression after neurotrauma in a mouse model of AD. The following MRI sequences were investigated: dynamic contrast‐enhanced (DCE) MRI, Fluid attenuated inversion recovery (FLAIR) MRI, Quantitative Susceptibility Mapping (QSM) and diffusion MRI.Method3xTg‐AD mice (Jackson Laboratory, ME) were bred and maintained at Boston University. Unanesthetized mice were pretreated with a non‐sedating dose of the analgesic buprenorphine (0.2mg/kg, i.p.) prior to TBI. Male and female 3xTg‐AD mice were subjected to left‐lateral closed‐head impact injury at 10‐12 weeks of age as described in our previous work (Tagge et al., 2018). MRI data were acquired at 1 day, 3 days, 1 month and 3 months post TBI. DCE‐MRI was analyzed using in‐house software programmed in Matlab (Mathworks, MA). The volume of white matter hyperintensity was measured using manual contours in ImageJ (NIH). QSM data was analyzed using JHU/KKI QSM Toolbox (Li et al, 2019). Diffusion MRS was analyzed in DSI Studio (http://dsistudio.labsolver.org). Age, gender matched 3xTg‐AD mice without TBI were used as controls.ResultIncreased blood‐brain permeability was detected by DCE‐MRI and changes of white matter susceptibility detected by QSM were observed in the subacute phase (1‐3 days) post TBI. Accelerated development of white matter hyperintensity was observed as early as 1 month post TBI.ConclusionMRI markers provide valuable measures of the integrities of blood‐brain barrier and white matter after neurotrauma in vivo, and have the potential to facilitate the management of neurotrauma subjects with a risk of accelerated AD development.
Use of cerebrospinal fluid biomarkers for accurate diagnosis of Alzheimer’s disease in a tertiary care memory center
Authors: Natalya Yarovinsky , Tanne David , Ben‐Hayun Rachel , Hadad Rafi , Levavi Michal , Kogan Olga , Raya Maison Abu , Aharon‐Peretz Judith 
Published: December 2023

AbstractBackgroundAccurate clinical‐biological diagnosis of dementia and of Alzheimer’s disease (AD) is important for exclusion of treatable modifiable conditions, to differentiate AD from conditions with similar clinical manifestations, and for consideration of novel disease‐modifying therapeutic agents. Recently, it has become possible to measure protein biomarkers that reflect the pathology of AD. Our aim was to examine our initial experience of running a “cognitive” CSF biomarker service and bank at our institute.MethodThe service operates since June 2020. All subjects underwent physical, neurological and cognitive evaluation, imaging and laboratory work‐up. Consenting patients presenting at young age or with atypical or unclear manifestations of cognitive and/or behavioral deterioration underwent lumbar puncture for CSF examination, tailored according to the clinical differential diagnosis [cells, protein, glucose, chloride, cytology, AD biomarkers‐ total tau (tTau), 181‐phosphorylated tau (pTau181), amyloid‐β42 (Aβ42)]. When appropriate, antibody analysis and microbiological studies were added.ResultAD biomarkers results were available for 63 subjects presenting with cognitive/behavioral impairment, mean age 59 (range 31‐78) years, 34 (54%) were men. Mean MMSE score was 21/30 (range 6‐30), mean MoCA score was 18/30 (range 6‐28). Pre CSF analysis, 27 (43%) subjects were clinically diagnosed with possible AD (CDAD) and 36 (57%) with clinically diagnosed possible non‐AD (CDNAD) (FTD, LBD, CBD, vascular disease, autoimmune encephalopathy, unclear etiology). In our sample 28 (44%) were biomarkers positive for AD. Among 27 subjects with CDAD in 5 AD was excluded and among 36 with CDNAD 6 were biomarker positive AD (clinical sensitivity 78%, false positive 18.5%, false negative 16.6%).ConclusionOur study emphasizes the added value of biomarker supported diagnosis in subjects with cognitive/behavioral impairment, to avoid incorrectly labeling AD or misdiagnosis and for disclosure recommendation in the era of disease‐modifying therapies.