bluuebunny/crossref_metadata_2025_split huggingface dataset:
Noninvasive and remote measurement of sleep‐active glymphatic function in the human brain by dynamic impedance spectro‐tomography
Authors: Iliff Jeffrey J , Levendovszky Swati Rane , Vanderweerd Carla , Jaffe Michael , Lowenkron Jeffrey , Singh Tarandeep , Giovangrandi Laurent , Lim Miranda , Dagum Paul 
Published: December 2023

AbstractBackgroundPerivascular glymphatic exchange contributes to the clearance of amyloid β, tau, and α synuclein primarily during sleep. Glymphatic function has been assessed in human populations solely through neuroimaging, including contrast‐enhanced magnetic resonance imaging (CE‐MRI). Using a newly developed investigational medical device (IMD) to measure brain parenchymal resistance to fluid flow by dynamic impedance spectro‐tomography, we evaluated the performance of this putative measure of glymphatic function against “gold‐standard” CE‐MRI.MethodHealthy 55‐65 y/o participants were enrolled in a cross‐over randomized control clinical trial encompassing one night of sleep/sleep deprivation followed by 4hr morning window of wake/sleep. Intravenous CE‐MRI was obtained prior to (T0) and following (T1) the 4hr window. Participants were instrumented with the IMD to measure continuous changes in brain parenchymal resistance (R). For the ROIs of interest, contrast enhancement (CE) was measured as the ratio of the T1/T0 MRI signal. The ratio CEp/CEd of anatomically proximal ROIs (CEp) to distal ROIs (CEd) was used to measure increasing (CEp/CEd ≤ 1) or decreasing (CEp/CEd > 1) net contrast movement. The predictive value of the R measured by the IMD, multiple EEG powerbands, and time spent in N2, N3 and REM sleep were tested against the CE‐MRI ROI ratios. Data from fourteen intervention periods were available for analysis.ResultIMD parenchymal resistance R predicted IV CE‐MRI contrast movement through blood, cerebrospinal fluid, and interstitial brain compartments (Table 1, Figure 1). EEG slow power predicted contrast movement into more proximal ROIs only. Other powerbands and hypnogram sleep stages were not predictive of contrast movement.ConclusionEEG powerbands (increased slow, reduced beta) were weakly associated with increased glymphatic exchange measured by CE‐MRI. Parenchymal resistance R measured by the IMD were robust predictors of contrast movement from proximal (ventricles, subarachnoid) CSF compartments, through parenchymal compartments (gray matter, white matter). These findings begin to validate IMD‐derived parenchymal R as non‐imaging measure of glymphatic function. Detection of glymphatic impairment in real‐world settings may permit (i) early identification of individuals at‐risk for developing sleep‐related Alzheimer’s disease pathology, and (ii) enable precision targeted enhancement of glymphatic function to enhance glymphatic function and pathological protein clearance.
Tau “islands” affects axonal transport in vitro and in vivo
Authors: Moretto Edoardo , Panzi Chiara , Stuart Skye , Huff Emily , Rocque Samantha De La , Schiavo Giampietro 
Published: December 2023

AbstractBackgroundTau is a protein abundantly expressed in neurons where it modulates the stability of axonal microtubules, thus contributing to the regulation of axonal transport of several organelles. Tau aggregates in a group of neurodegenerative diseases named tauopathies, which include frontotemporal dementia (FTD) and Alzheimer’s disease. Recent in vitro work has uncovered the existence of tau “islands”, a microtubule‐bound multimeric state of tau, which is distinct from pathological aggregates. However, whether these structures exist in intact neurons remains unclear.MethodWe investigated both cultured mouse neurons and mice in vivo, using immunoistochemistry, live imaging and two photon microscopy.Resultswe found that human tau showed regions of higher density along axons, reminiscent of tau islands. FTD‐linked mutations, known to increase pathological phosphorylation and aggregation of tau, induces larger islands, an effect that is reversed by inhibition of p38 MAPK, known to phosphorylate tau at multiple sites. Functionally, axonal transport of BDNF‐containing secretory granules is affected by FTD‐linked mutant tau as assessed both in vitro and in vivo by using a new assay based on two‐photon microscopy. Interestingly, this impairment occurred very early on, before overt tau aggregation. Inhibition of p38 MAPK was able to partially rescue the defects in axonal transport both in vitro and in vivo.ConclusionOur data suggests that tau island size regulates axonal transport, an effect dependent on tau phosphorylation. Inefficient organelles transport may have severe consequences on the activity and plasticity of neuronal circuits. The evidence that reducing tau phosphorylation by inhibiting p38 MAPK potentiated axonal transport points towards inhibition of p38 MAPK as a promising therapeutic strategy in tauopathies.
Blood‐based biomarker profiles of community cohort of rural‐dwelling older adults
Authors: Miller Justin B , Wong Christina G. , Kinney Jefferson W , John Samantha E , Cummings Jeffrey L. , Caldwell Jessica ZK , Calvin Kirsten , Pasia Lorenzo G , Ritter Aaron 
Published: December 2023

AbstractBackgroundGeography may influence Alzheimer’s disease risk, but there have been few prospective studies with biomarker characterization among rural‐dwelling individuals. We present preliminary biomarker data from the rural cohort followed by the Nevada Exploratory Alzheimer’s Disease Research Center, with comparisons to a harmonized urban cohort.MethodCommunity‐dwelling adults over age 50 are enrolled and followed annually. Core assessments include medical exam, cognitive assessment, and blood‐based biomarkers of neurofilament light (NFL), phosphorylated tau (pTau181), and glial fibrillary acidic protein (GFAP) measured from plasma samples via the Quanterix Single Molecular Array (Simoa) HD‐X platform. Biomarker values exceeding 3 standard deviations from the combined sample mean were removed from analyses. Primary comparisons included ANCOVAs with main between‐group effects of cohort and cognitive status, accounting for both age and sex; interactions between cohort and impairment status were also explored. Correlations between biomarkers and cognitive screening (MoCA) were also assessed. Raw biomarker data were log transformed prior to analysis.ResultNFL was associated with age (F(1,143) = 53.26, p<.001) main effects of impairment status were found (F(1,143) = 9.81, p<.001) but there was no association with sex or differences between urban and rural cohorts. The interaction between impairment status and cohort was significant, such that NFL concentrations were lower for cognitively normal rural‐dwellers, but higher among those with impairment (F(1,143) = 9.95, p<.01). GFAP was associated with age (F(1,136) = 31.05), p<.001) and sex (F(1,136) = 12.46), p<.001), but there were no main effects of cohort or impairment status, and there was no interaction. Tau was associated with age (F(1,153) = 11.08, p<.01) but not sex, and there were no main effects of cohort or impairment status, and no interaction was found. NFL was not correlated with cognition in the urban cohort (r = ‐.11), but was inversely correlated in the rural cohort (r = ‐.34). All other correlations were significant.ConclusionRural‐dwelling older adults with cognitive impairment had higher concentrations of NFL compared to an urban cohort from the same region, though among cognitively unimpaired individuals, rural‐dwellers had lower concentrations of NFL. There were no rural‐urban differences in pTau or GFAP. Neurodegeneration may be a more sensitive indicator of cognitive impairment relative to other biomarkers, which may facilitate detection of geographic health disparities.
Association of periodontal condition with cognitive impairment and the mediating role of accelerated biological aging among US older adults
Authors: Qi Xiang , Wu Bei 
Published: December 2023

AbstractBackgroundIncreasing evidence has shown the associations between periodontitis and cognitive impairment or dementia; however, few studies have explored the role of accelerated biological aging that affects this association. Biological aging is the gradual and progressive decline in system integrity that occurs with advancing age. In this study, we examined the mediating effect of biological aging on the association between periodontal conditions and cognitive impairment in US older adults.MethodWe analyzed data from 2,186 participants aged 60 and older from the US National Health and Nutrition Examination Survey 2011‐2014. Data included sociodemographic, behavioral, and health‐related characteristics, periodontal status (measured by mean clinical attachment loss and pocket depth), blood‐chemistry measures of biological age (using KDM‐biological age and PhenoAge algorithms), and cognitive functioning (measured by Digit Symbol Substitution Test). We created an accelerated biological aging measure using residuals from regressing each blood‐chemistry measure on chronological age. The biological ages’ residual discrepancies with chronological age were defined as the biological age accelerations (BAA). Mediation analysis, weighted for complex survey design, assessed the effect of BAA on the association between periodontal conditions and cognitive functioning.ResultAfter adjusting for covariates, participants with periodontitis exhibited greater KDM BAA (β [SE] = ‐0.40 [0.17]), PhenoAge BAA (β [SE] = ‐0.57 [0.21]), and lower level of cognitive function (β [SE] = ‐1.50 [0.33]) than those without periodontitis. Both KDM and PhenoAge BAA were significantly associated with lower cognitive functioning (β [SE] = ‐0.27 [0.10] and β [SE] = ‐0.29 [0.07]), mediating 11.0% and 9.7% of the total effects of periodontitis on cognitive functioning, respectively. Furthermore, KDM and PhenoAge BAA mediated 11.7% and 5.8% of the association between mean pocket depth and DSST, respectively.ConclusionOur findings suggest that periodontitis is partially associated with worse cognitive functioning through accelerating the biological aging process. Efforts to improve oral health or slow biological aging have the potential to help reserve cognitive health in later life.
The association between microstructural MRI biomarkers and sequential amyloid and tau‐related cortical changes in asymptomatic elderly individuals
Authors: Weston Philip SJ , Coath William , Brown Thomas M. , Scott Catherine J , Malone Ian B , Arstad Erik , Awais Ramla , Sander Kerstin , Thomas David L , Dickson John , Schöll Michael , Richards Marcus , Fox Nick C , Zhang Hui , Cash David M , Schott Jonathan M 
Published: December 2023

AbstractBackgroundIn Alzheimer’s disease, early amyloid‐β and tau deposition may have differential downstream effects on synaptic function and neuronal loss in a stage‐dependent manner. Amyloid‐related synaptic changes are thought to precede tau accumulation, which starts in the medial temporal lobe before propagating and leading to neurodegeneration. We explored whether microstructural MRI measures can detect these different sequential cortical changes.MethodSeventy‐nine healthy, asymptomatic individuals, recruited from the Insight 46 study of the British 1946 birth cohort underwent combined PET/MR with [18F]florbetapir Aβ‐PET at ∼73yrs, and [18F]MK‐6240 tau‐PET at ∼76yrs. Standard uptake value ratios were calculated using a whole cerebellar reference for florbetapir and an inferior cerebellar reference for MK‐6240. Multi‐shell diffusion MRI was acquired; neurite orientation dispersion and density imaging was used to quantify neurite density (NDI) and orientation dispersion (ODI, a proxy measure of dendritic morphology/complexity), with DTI measuring mean diffusivity (MD), a less specific measure of degenerative change. PET and microstructural MRI biomarkers were assessed in a neocortical composite ROI and across Braak stages.ResultThirty‐six participants were amyloid positive, 18 of whom were tau positive (eight Braak stage 1‐2, four Braak 3‐4, six Braak 5‐6). Across all participants, in the neocortical composite, significant differences between amyloid positive and amyloid negative individuals were found in both tau PET (p = 0.0092) and ODI (p = 0.030) but not for other measures. Within the amyloid positive group, in the cortical composite, significant differences in MD (p = 0.0093) but not ODI were seen when comparing those who were tau positive and negative. In the amyloid positive group, there was an association between tau PET and MD in the MTL (Braak 1‐2) (r = 0.34, p = 0.040) and Braak 3‐4 (r = 0.37, p = 0.025), with an association between tau and ODI (r = 0.48, p = 0.0031) in Braak 3‐4 only. After adjusting for volume, only the association between tau PET and ODI in Braak 3‐4 remained (p = 0.038).ConclusionOur results are consistent with amyloid deposition causing dendritic/changes (as assessed by ODI) with consequent synaptic dysfunction. Later tau propogation is then associated with frank neuronal breakdown (as measured by MD). dMRI cortical imaging biomarkers have the potential to provide proxy measures of underlying AD stage/pathology prior to symptom onset.
Independent associations of plasma GFAP with amyloid‐β and tau in Alzheimer’s disease
Authors: Jia Wan Lu , Rahmouni Nesrine , Tissot Cécile , Servaes Stijn , Therriault Joseph , Macedo Arthur C. , Arias Jaime Fernandez , Wang Yi‐Ting , Lussier Firoza Z , Kunach Peter , Gauthier Serge , Zimmer Eduardo R , Karikari Thomas K , Benedet Andrea L. , Ashton Nicholas J. , Zetterberg Henrik , Pascoal Tharick A. , Blennow Kaj , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundGlial fibrillary acidic protein (GFAP) is a reactive astrogliosis biomarker, shown to increase in individuals with preclinical Alzheimer’s disease (AD). First thought to be a great marker of amyloid‐β (Aβ) pathology, recent post‐mortem research has linked it to tau accumulation only. Here we investigate the independent associations of plasma GFAP with imaging markers of AD along the disease spectrum.Method126 individuals from TRIAD cohort underwent [18F]MK6240 tau‐PET and [18F]AZD4694 Aβ‐PET and plasma GFAP assessment using an in‐house assay. Voxel and region of interest regression models evaluated the relationship between PET tracers and plasma GFAP. Models with [18F]AZD4694‐PET as the outcome were adjusted for [18F]MK6240‐PET voxel‐wise and vice‐versa. All models were corrected for age and sex, and RFT was used to correct for multiple comparisons.ResultPlasma GFAP was associated with [18F]AZD4694 signal throughout the cortex (Figure1A), independently of [18F]MK6240. Additionally, it was positively correlated with [18F]MK6240 in the medial temporal and occipital lobes and the anterior cingulate cortex, independently of [18F]AZD4694 (Figure1B). Voxel‐wise findings were confirmed by region‐of‐interest‐based analyses.ConclusionOur findings indicate that plasma GFAP is independently associated with both Aβ and tau pathologies in AD. Aβ‐PET showed associations throughout the entire cortex, suggesting its effectiveness as a reliable marker of Aβ pathology across the AD spectrum. On the other hand, tau‐PET correlations were observed in specific regions associated with memory and behavioral impairments that exhibit early deposition of tau. Overall, these results demonstrate that GFAP, an astrogliosis marker, is independently associated with Aβ and tau.
Dementia associated with early‐onset Parkinson’s disease: Description of a family case in Colombia
Authors: Lopez Greizy , Gelvez Nancy , Duran Clemencia , Garcia Deissy Milena , Reyes Pablo A , Matallana Diana 
Published: December 2023

AbstractBackgroundParkinson’s Disease (PD) is a motor neurodegenerative disorder of the dopaminergic neurons in the substantia nigra1. One of the frequent complications is dementia and often is a late symptom1,2. Some studies suggest that around 10% of patients with PD develop dementia per year2,3. Mutations in PLA2G6 are responsible of PARK14, an autosomal recessive L‐DOPA responsive dystonia/parkinsonism with early/adult onset4. This phenotype presents a high clinical variability, which consists in the occurrence of cerebral and cerebellar atrophy, iron accumulation in the basal ganglia, and cognitive decline4. In this study, we describe the genotype of two brothers diagnosed with early onset PD and a phenotype with FTD‐like characteristics.MethodA complete clinical evaluation consisting of geriatric, psychyatric, neurologic and neurpsychologic evaluation, was carried out in two affected male individuals, and their family. NGS was performed (PD targeted panel, WES, WGS) and MLPA on the two affected individuals.ResultThe two affected individuals were diagnosed around their thirties, presenting classic motor symptoms of PD. Subsequently, dementia associated to frontotemporal disease was diagnosed. No iron accumulation in the basal ganglia was found in either of the affected siblings. Genetic tests showed the pathogenic variant in heterozygous state c.2132C>G, p.Pro711Arg in PLA2G6 gene in the two affected brothers and their healthy mother.ConclusionAtypical frontotemporal dementia in two siblings with early‐onset PD is described. Additional studies should be performed to identify another variant or another gene in this family. Some studies have risen the hypothesis that even heterozygous PLA2G6 mutations may cause PARK144.References:1. Hanagasi HA, Tufekcioglu Z, Emre M. Dementia in Parkinson’s disease. J Neurol Sci. Mar 15 2017;374:26‐31. https://doi.org/10.1016/j.jns.2017.01.012
2. Garcia‐Ptacek S, Kramberger MG. Parkinson Disease and Dementia. J Geriatr Psychiatry Neurol. Sep 2016;29(5):261‐70. https://doi.org/10.1177/0891988716654985
3. Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson’s disease. Brain Pathol. May 2010;20(3):633‐9. https://doi.org/10.1111/j.1750-3639.2009.00369.x4. Ferese R, Scala S, Biagioni F, et al. Heterozygous PLA2G6 Mutation Leads to Iron Accumulation Within Basal Ganglia and Parkinson’s Disease. Front Neurol. 2018;9:536. https://doi.org/10.3389/fneur.2018.00536
Altered resting state hippocampal connectivity associated with amyloid and tau in older adults without dementia from a population‐based cohort study
Authors: Roberts Anna T , Andreescu Carmen , Cohen Annie , Villemagne Victor L , Lopresti Brian J. , Nadkarni Neelesh K. , Minhas Davneet S , Laymon Charles M , Snitz Beth E. , Karim Helmet T. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by amyloid beta plaques and tau‐containing neurofibrillary tangles with disrupted (high and low) resting state hippocampal connectivity. One potential factor that may underlie these differences is that early stages of disease may contribute to greater connectivity and later stages may contribute to lower connectivity (i.e., quadratic associations between amyloid/tau and connectivity). Early stages may be associated with greater recruitment of intranetwork connectivity to compensate, which fails at later stages. Late stages may be associated with greater recruitment of internetwork connectivity, that fails in advanced cognitive impairment. Understanding these dynamics may help us understand resilience to amyloid and tau in cognitively unimpaired individuals.MethodWe recruited 115 adults >65 years old (67‐96, mean 76years) from a population‐based study into a neuroimaging sub‐study. The study area is a formerly heavy manufacturing industrial small‐town area. Participants (106 (92%) CU with CDR = 0) underwent PET imaging for amyloid (PiB) and tau (AV‐1451) and global SUVR measures were computed after appropriate preprocessing. Participants underwent resting state fMRI and hippocampal connectivity was computed for the left/right and anterior/posterior hippocampus. Regression analyses between connectivity and both linear and quadratic terms for amyloid and tau were adjusted for age, sex, race, and education. We adjusted for multiple comparisons using SnPM with FWE correction with α = 0.05 (p‐value threshold of 0.001).ResultWe found a negative quadratic association between left anterior hippocampus with default mode network (DMN) including the posterior cingulate and supramarginal gyrus, where greater amyloid and lower amyloid was associated with low connectivity. Similar effects were found for the right anterior hippocampus. Right anterior hippocampus to cuneus connectivity shows positive U‐shape with amyloid but negative linear relationship with tau. Greater right anterior hippocampus‐inferior parietal and right posterior hippocampus‐inferior temporal connectivity was associated with greater tau. Left posterior hippocampus to left middle temporal showed negative U‐shape with tau.ConclusionAmyloid and tau showed complex inverse U‐shaped associations between heightened intranetwork connectivity and moderate amyloid/tau, but low connectivity with higher severity. Internetwork connectivity was heightened with greater tau. These may reflect altered connectivity due to changes in amyloid and tau in older adults without dementia.
Hearing the Older Adults and Caregivers Voice in Medication Optimization Initiatives
Authors: Brandt Nicole J 
Published: December 2023

AbstractBackgroundEngaging older adults, caregivers and family is necessary to produce relevant and meaningful evidence. Patient‐centered‐outcomes research (PCOR) engages these individuals as research partners. For instance, the process of shared decision‐making about deprescribing (reducing or stopping potentially inappropriate medications) between people living with dementia and their carers (consumers), and clinicians, is complex.MethodVarious tactics were employed by the Elder Care Medicine Network (ECMN) and stakeholder steering groups from USA and Australia. These initiatives describes efforts to increase capacity of local communities – older adults, their caregivers, healthcare providers and researchers – to participate in medication related PCOR as well as the development of a tool (PRIME) to help with deprescribing medications for individuals with dementia.ResultThere are over 120 active participants in the ECMN. After they shared their PCOR training needs, trainings were held as Discussion sessions where Council members and network participants shared their medication experiences and talked about participating on a PCOR research team. Network participants also identified what they felt were meaningful research questions on medication‐related PCOR (video). Additionally the PRIME tool was developed via an iterative process utilizing one‐to‐one semi‐structured interviews and a focus group session with 39 participants (people living with dementia, carers, and clinicians) to determine the usability and comprehensibility of the PRIME tool. Iterative changes were made to improve the content and layout of the tool.ConclusionThese two initiatives illustrate the importance of co‐design and incorporating the older adults and caregivers voice in medication optimization efforts in individuals with dementia.