bluuebunny/crossref_metadata_2025_split huggingface dataset:
Independent associations of plasma Aβ42 and plasma neurofilament light with white matter hyperintensity volume in non‐demented older individuals
Authors: Chatterjee Ankita , Saloner Rowan , Asken Breton M. , Chan Brandon , Lago Argentina Lario , Casaletto Kaitlin B. , Elahi Fanny M , Tsuei Torie , Rojas Julio C. , Kramer Joel H. 
Published: June 2023

AbstractBackgroundPlasma biomarkers have potential to capture features of Alzheimer’s disease (AD)‐related pathophysiology, but less is known about how they might associate with an imaging measure of cerebral small vessel disease (cSVD). The present study examined independent and combined associations of plasma markers of AD pathology (Aβ42, P‐tau181), axonal damage (neurofilament light [NfL]), and astrocytic activation (glial fibrillary acidic protein [GFAP]) with white matter hyperintensity (WMH) volume in adults without dementia.MethodPlasma Aβ42, P‐tau181, NfL, and GFAP (Quanterix Simoa) were measured in 151 older adults without dementia (124 cognitively unimpaired, 27 mild cognitive impairment; aged 52 ‐ 91, 57% female, 95% non‐Hispanic white) who underwent MRI with T2‐weighted FLAIR. Controlling for age, sex, APOE genotype, and intracranial volume, linear regressions first examined WMH volume as a function of each plasma biomarker separately, and next in a combined model with independent and interactive effects of biomarkers associated with WMH from the individual models.ResultIn individual models, higher WMH volumes were associated with lower plasma Aβ42 (β = ‐0.17, p = 0.032, model R2 = 19.4%) and higher NfL concentrations (β = 0.21, p = 0.013, model R2 = 20.3%). Plasma P‐tau181 (β = ‐0.015, p = 0.851) and GFAP (β = 0.05, p = 0.593) were not significantly associated with WMH volume. Aβ42 and NfL did not demonstrate an interaction but both remained independently associated with WMH volume (Aβ42: β = ‐0.19, p = 0.015; NfL: β = 0.24, p = 0.005; model R2 = 22.7%). No significant interactions between other biomarkers were found.ConclusionPlasma Aβ42 and NfL concentrations associate with burden of cSVD as quantified by WMH load on MRI in non‐demented older adults. As a non‐specific marker of axonal injury, plasma NfL may have utility in studies of brain degeneration related to cSVD. Future studies are warranted to identify factors that may be mediating the effect of plasma amyloid on WMH.
NeuroMET Memory Metric: Improving accuracy and comparability with crosswalks
Authors: Melin Jeanette , Cano Stefan , Göschel Laura , Flöel Agnes , Pendrill Leslie ,   This project (EMPIR 18HLT9 NeuroMET2) has received funding from the EMPIR programme co‐financed by the Participating States and from the European Union’s Horizon 2020 research and innovation programme
Published: June 2023

AbstractBackgroundThe ability to measure, track over time, and compare memory ability for people with neurodegeneration is important. However, currently, full comparability of memory test data is limited by a lack of quality assurance of memory measurements. At AAIC 2021, we presented a preliminary item bank to assess memory, composed by selecting items from legacy tests according to metrological principles through use of the Rasch model and with item equivalence based on entropy.MethodHere, we demonstrate direct comparability of measurements generated from different tests, with the new NeuroMET Memory Metric comprising 87 selected items for task difficulty from: the Corsi Block Test, Digit Span Test, Rey’s Auditory Verbal Learning Test, Word Learning List from the CERAD test battery and the Mini Mental State Examination. Data were collected from the European EMPIR NeuroMET and the SmartAge studies recruited at Charité Hospital (Healthy controls n = 92; Subjective cognitive decline n = 160; Mild Cognitive Impairment n = 50; and Alzheimer’s Disease n = 58; age range 55‐87).ResultsThe Rasch analysis showed well‐targeted items for all participants’ abilities; good fit to the measurement model, with 83 items (95%) having fit residuals within the expected range and satisfactory unidimensionality, and item reliability of 0.96. The full item bank comprising 87 short‐term memory items gave a person reliability of 0.85. Subsequently, a conversion table was created linking the raw scores from the legacy tests to the common NeuroMET Memory Metric and to individual legacy tests.ConclusionLegacy memory tests have previously proven useful in clinical practice and research, and will continue to be used, but have to date been metrologically limited. The provided conversion table, linking these legacy memory tests to a metrologically assured scale, viz., the NeuroMET memory metric, remedies this deficiency. The NeuroMET memory metric will be included in the first ever prototype of a metrological validated app used to deliver memory tests. Clinicians and researchers will be able to select sets of items to produce data, via a scoring algorithm for transforming patient responses to measures, in a common frame of reference.
White matter fractional anisotropy in a nonhuman primate model of early Alzheimer’s Disease‐like neuropathology: Relationships with social status and physiologic measures of stress responses
Authors: Frye Brett M. , Craft Suzanne , Register Thomas C. , Kim Jeongchul , Whitlow Christopher T. , Barcus Richard A. , Lockhart Samuel N. , Sai Kiran K Solingapuram , Shively Carol A. 
Published: June 2023

AbstractBackgroundPsychosocial stress is associated with micro‐ and macrostructural brain changes that may increase risk of Alzheimer’s disease (AD). White matter (WM) appears particularly vulnerable, and changes in white matter integrity are an early sign of AD pathogenesis. Cynomolgus macaques (Macaca fascicularis) have complex central nervous systems and naturally develop early AD‐like neuropathology with age. Female macaques form social status hierarchies in which subordinates exhibit behavioral and physiological signs of stress, and increased stress‐related pathologies similar to humans. Nonhuman primate studies provide a useful platform in which to assess relationships between stress and brain health is a well‐controlled environment with limited outside influences. Thus, these nonhuman primates are useful translational models for studying relationships of psychosocial stress with early AD‐like neuropathology.MethodUsing diffusion tensor imaging, we examined the relationship between psychosocial stress and fractional anisotropy (index of WM microstructural integrity (FA)) in 38 middle‐aged female cynomolgus macaques living in small social groups. Subjects were classified as either dominant or subordinate based upon the outcomes of agonistic interactions. FA in several regions of interest (ROIs): splenium, body, and genu of the corpus callosum (CC), frontal, temporal, occipital, and total cerebral and cerebellar white matter was assessed in relation to social status and several contemporaneous measures of stress physiology (blood pressure, resting cortisol, and heart rate variability (HRV)).ResultRepeated measures ANOVA using left and right ROIs as a repeated measure showed that dominants had significantly higher FA than subordinates in the genu and splenium of the CC, and the occipital and frontal cortices (all p<0.05). Dominants also had higher FA, on average, in the body of CC (p = 0.07) and cerebrum (p = 0.10), although these differences were not significant. Dominants and subordinates did not differ in temporal or cerebellar FA (both p>0.7). FA was inversely correlated with blood pressure, directly correlated with HRV (p’s<0.05), but not correlated with serum cortisol.ConclusionPsychosocial stress of subordination, as well as physiologic indices of stress responses, was associated with diminished WM integrity in several brain regions. These studies lay the groundwork for investigations of interventions on psychosocial stress to reduce AD risk later in life.
Subcortical atrophy imaging biomarker performance across the sporadic and genetic frontotemporal dementias
Authors: Gordon Elizabeth , Bocchetta Martina , Nicholas Jennifer M , Cash David M , Rohrer Jonathan D. 
Published: June 2023

AbstractBackgroundFrontotemporal dementia (FTD) is a common cause of young‐onset dementia, with promising disease‐modifying candidates. Cortical signatures are well established; however, comprehensive longitudinal investigations of subcortical atrophy are limited and sample size estimates to inform imaging biomarker choice are lacking. Therefore, the current study investigated the relative utility of automated subcortical atrophy measures to detect putative disease‐modifying treatment effects in clinical, genetic and pathologically‐confirmed FTD.MethodLongitudinal registration and segmentation algorithms were applied to a cohort of 262 people, 184 of whom were diagnosed with FTD, to measure atrophy in the amygdala, hippocampus, caudate and thalamus. Clinical diagnoses were behavioural variant FTD (n = 66) and primary progressive aphasia (PPA, n = 118), comprising semantic variant PPA (n = 45), non‐fluent variant PPA (n = 45), logopenic variant PPA (n = 21), and PPA‐not otherwise specified (n = 7). Fifty‐three patients had either a known pathogenic mutation (in the MAPT, C9orf72 or GRN genes) and/or underlying tau or TDP‐43 pathology confirmed at post‐mortem. Seventy‐eight cognitively normal controls were included for comparison. Sample size estimates were computed to explore the relative feasibility of subcortical atrophy measures to track disease progression and detect treatment‐related effects across the different subgroups.ResultRelatively distinct patterns of significantly increased atrophy across the amygdala, hippocampus, caudate and/or thalamus were detected (p < 0.001) for all sporadic, genetic, and pathology‐confirmed FTD subgroups, with a strong left‐dominant pattern evident for PPA‐NOS and GRN patients. The best performing marker (as determined by lowest sample size required to detect a treatment effect) varied by subgroup supporting the importance of informed regional biomarker choice based on the population enrolled. Measures of the caudate and thalamus performed particularly well across all the subgroups, producing estimates well below 100 patients per treatment arm. The left hippocampal BSI (boundary shift integral) measure produced the lowest estimate overall in PPA‐NOS, with 12 individuals required to detect a 30% reduction in atrophy.ConclusionThis work confirms the relative utility of subcortical atrophy measures across the FTD spectrum and provides valuable sample size information to inform non‐invasive biomarker choice for sporadic and genetic FTD trials.
Preliminary biological evaluations of first brain‐penetrant GPR119‐based radiotracer in rodents and non‐human primates
Authors: Bansode Avinash , Damuka Naresh , Krizan Ivan , Miller Mack , Bashetti Nagaraju , Kumar JV Shanmukha , Ma Tao , Shively Carol A. , Lockhart Samuel N. , Whitlow Christopher T. , Craft Suzanne , Jorgensen Matthew J. , Sai Kiran K Solingapuram 
Published: June 2023

AbstractBackgroundG‐protein‐coupled receptors (GPCRs) plays a key role in regulating glucose metabolism. While GPR119 (an important GPCR) agonists have shown potential for improving neurologic and cognitive function in patients with AD and type2 diabetes mellitus (T2DM), clinical interventions targeting GPR119 will require accurate in vivo measures such as PET imaging. We recently synthesized a series of novel piperdine analogs, identifying two analogs (T1 and T2) with high GPR119 binding potency (2‐5 nM) for PET radiochemistry. Here we report their radiochemistry and initial biological evaluations in neuronal cells, normal rodents, and monkeys (vervets).Method[18F]T1/T2 radiochemistry was performed in TRASIS‐AIO automated module following [18F]¯‐based nucleophilic substitution of corresponding precursors. [18F]T1 and T2 in vitro assays were performed in three patient‐derived cell lines with different GPR119 expression (MDM‐MD‐231<NCI‐H1716<HepG2), with and without GPR119 agonists and non‐radioactive T1/T2. Dynamic 0‐60 min brain microPET/CT imaging and biodistribution were performed in normal balb/c mice (n = 4). Healthy adult female vervets (n = 6, 4.5‐6.7 kg) underwent 0‐90 min brain PET imaging. Standard uptake value (SUVmax) and time‐activity curves (TACs) were calculated for whole brain PET/MR images.ResultBoth [18F]T1 and T2 were produced in high radiochemical purities (>98%) and specific activities (∼3800‐4500 mCi/µmol), decay corrected to end of synthesis. Radioactive cell uptake was lower in MDM‐MD‐231 cells (lowest GPR119 expression) and higher in HepG2 cells (higher GPR119 expression); uptake also significantly increased with GPR119 agonists and T1/T2 treatments compared to baseline. [18F]T2 showed slightly better brain uptake in mice compared to [18F]T1 (SUVmax = 0.35±0.07 Vs. 0.55±0.09 g/mL). Biodistribution of [18F]T2 (%ID/mg = 1.01±0.09) also showed high brain uptake. SUVmax (avg = 2.6±0.1 g/mL) and TACs of both [18F]T1 and [18F]T2 in monkey brains demonstrated rapid distribution across BBB within 10 min and favorable clearance within 90 min of tracer injection (Fig 1).ConclusionRadiochemistry was successfully automated and optimized. Cell uptake showed direct relationships between radiotracer uptake and GPR119 expression. MicroPET imaging, biodistribution in rodents and monkey PET imaging demonstrated excellent brain uptake and favorable pharmacokinetics, indicating BBB penetration. These data suggest for the first time that [18F]T1 and T2 have potential for imaging GPR119 in brains of humans with AD or T2DM.
Association of type 2 diabetes mellitus and its management with cognitive function in adults: A prospective cohort study
Authors: Chen Xiao , Li Wanlu , Huang Yuhui , Tao Yang , Huang Liyan , Yang Jiaxi , Shen Jiadong , Ma Yanan , Liu Zuyun , Xu Xin , Xu Xiaolin , Zong Geng , Yuan Changzheng 
Published: June 2023

AbstractBackgroundType 2 Diabetes Mellitus (T2DM) has been associated with lower levels of cognitive function in older adults. However, evidence on the potential role of T2DM management in age‐related cognitive function is limited. To explore the prospective association of T2DM and its management with cognitive function among middle‐aged and older Chinese adults.MethodThis study included 7,230 participants without baseline brain damage, mental retardation, or memory‐related diseases from the China Health and Retirement Longitudinal Study (CHARLS) in 2011‐2012. Fasting plasma glucose and self‐reported information on T2DM diagnosis and treatment was assessed at baseline. Participants were then categorized into normoglycemia, impaired fasting glucose (IFG), and T2DM (including untreated T2DM and treated T2DM) groups. Cognitive function, including episodic memory and executive function, was assessed by the modified Telephone Interview for Cognitive Status (TICS) every two years until 2015. We used the generalized estimating equation (GEE) model to examine the association of baseline T2DM status and cognitive function in succeeding years.ResultCompared to those with normoglycemia, participants with T2DM tended to have lower level of overall cognitive function (β = ‐0.23, 95% CI: ‐0.43, ‐0.02) after controlling for demographic variables, lifestyles, follow‐up time, and major clinical factors. In particular, the strong association was mainly observed for those with untreated T2DM (β = ‐0.31, 95% CI: ‐0.54, ‐0.07), especially in the domain of executive function (β = ‐0.22, 95% CI: ‐0.39, ‐0.06) and among those ≥60 years (β = ‐0.58, 95% CI: ‐0.91, ‐0.23). In general, individuals with IFG and treated T2DM had similar levels of cognitive function with normoglycemia participants.ConclusionOur findings supported the detrimental role of T2DM especially untreated T2DM in cognitive function among middle‐aged and older adults. Screening and early treatment for T2DM are warranted for maintaining better cognitive function in later life.
Detection of tau‐related structural connectivity changes in Alzheimer’s disease
Authors: Chen Qianyun , Deng Min , Abrigo Jill , Shi Lin , Chu Winnie C.W. 
Published: June 2023

AbstractBackgroundStructural connectivity assessed by diffusion tensor imaging (DTI) is reportedly associated with tau pathology in Alzheimer’s disease. In this study, we aimed to determine whether structural connectivity derived from DTI can reveal tau positivity at the individual level by utilizing a machine learning classifier.MethodAll data were collected from Alzheimer’s Disease Neuroimaging Initiative Phase 3. Sixty subjects (27 females; age range, 56‐94 years old) who underwent tau positron emission tomography (PET) and DTI scans at baseline were included. Tau pathology was assessed by 18F‐Flortaucipir standardized uptake value ratio PET in Braak stage composite regions. The cutoff point denoting positivity was set at 1.23 (Jack et al. 2017), yielding 30 scans each for normal and abnormal scans. DTI scans were acquired with 6 b0 and 48 diffusion‐weighted volumes with b = 1000 s/mm2 at 2.7 × 2.7 × 2.7 mm3 resolution and corrected for head motion and eddy‐current‐induced artifacts. Whole‐brain white‐matter fiber was tracked by deterministic tractography using DSI Studio under Q‐space diffeomorphic reconstruction scheme. The brain was parcellated into 120 regions‐of‐interest (ROIs) based on Automated Anatomical Labeling atlas 2, and each ROI served as a node of the network. Pairwise connectivity strength was quantified by the number of tracts connecting two ROIs and populated as a 120 × 120 connectivity matrix, serving as features for the following classification. A support vector machine classifier with the radial basis function kernel was trained for classification with stratified 10‐fold cross‐validation. Performance was evaluated by accuracy, sensitivity, and specificity.ResultThe average classification accuracy, sensitivity, and specificity were achieved at 65.0%, 86.7%, and 23.2% respectively.ConclusionStructural connectivity achieved high sensitivity in the detection of tau positivity, but it may not enable accurate classification at the individual level.
Down regulation of Akt/mTOR signaling pathway proteins in hippocampus of Alzheimer’s disease mouse model
Authors: Kommaddi Reddy Peera , Gowaikar Ruturaj , Singh Kunal , P A Haseena , Ravindranath Vijayalakshmi 
Published: June 2023

AbstractBackgroundAkt and mechanistic target of rapamycin (mTOR) signaling pathways are implicated in AD pathology. Activation of these pathways by external cues facilitates new protein synthesis at the synapse which leads to the synaptic plasticity. We have demonstrated that activity dependent Akt1 mediated new protein synthesis is abolished in primary cortical neurons of APP/PS1 mice. However, the molecular underpinnings for the impairment of new protein synthesis at the synapse are still elusive. Our aim is to understand the molecular mechanisms prior to manifestation of pathological symptoms by examining the Akt1 and mTOR signaling cascades and new protein synthesis in hippocampus of WT and APP/PS1 male mice.MethodsWe isolated post nuclear supernatant (PNS) and synaptosomes from brain cortices of WT and APP/PS1 mice at different ages. Synaptosomes and PNS were resolved on SDS‐PAGE and immunoblotted against respective antibodies. Further, synaptoneurosomes were also prepared from hippocampus and performed 35S methionine incorporation assay without or with KCl stimulation. Statistical comparisons were performed using two‐way ANOVA followed by Tukey’s post‐hoc test or two‐tailed Mann‐Whitney U test.ResultsWe observed that pAkt1, pGSK3β, pmTOR, pS6 ribosomal protein, p4E‐BP1 levels are significantly decreased in both post nuclear supernatant (PNS) and synaptosomal fractions isolated from hippocampus of one month old (presymptomatic) APP/PS1 compared to WT male mice. Further, activity dependent new protein synthesis at the synapse was significantly impaired in synaptoneurosomes isolated from hippocampus of presymptomatic APP/PS1 mice, and this deficit is sustained at young adults (three months). However, no impairment was observed in basal protein synthesis at both ages in hippocampus of APP/PS1 compared to WT male mice. Down regulation of Akt1 precludes synaptic activity dependent protein translation at the dendrites but not in the soma in hippocampal neurons from APP/PS1 mice compared to WT mice.ConclusionsOur finding demonstrate that the dysregulation of Akt1/mTOR and its downstream signaling molecules in hippocampus contributes to synaptic dysfunction in AD through loss of activity dependent new protein synthesis at the synapse in hippocampus which is essential for synaptic plasticity and maintenance.
Vascular and microstructural markers of cognitive pathology
Authors: Coffin Claudia Ashlyn , Suerken Cynthia , Bateman James R. , Whitlow Christopher T. , Williams Benjamin J. , Espeland Mark A. , Sachs Bonnie C. , Cleveland Maryjo , Yang Mia , Rogers Samantha D. , Hayden Kathleen M. , Baker Laura D , Williamson Jeff D. , Craft Suzanne , Hughes Tim M. , Lockhart Samuel N. 
Published: June 2023

AbstractBackgroundArterial stiffness may play a role in the development of dementia, presumably through its effects on white matter integrity and hyperintensities (WMH). However, relationships among arterial stiffness, white matter microstructure, and WMH volumes remain poorly understood. Arterial stiffness increases monotonically with age and its increase is accelerated by cardiometabolic disorders (e.g., hypertension, metabolic syndrome, diabetes). Further exploration of these relationships is key to the development of targeted therapies, early management, and detection.MethodArterial stiffness was measured using carotid‐femoral pulse wave velocity (cfPWV) in ADRC participants with baseline systolic blood pressure (SBP) measurements, detailed cognitive testing, cognitive adjudication, and brain MRI. We examined associations of cfPWV and SBP with cognitive function (Montreal Cognitive Assessment [MoCA], Preclinical Alzheimer’s Cognitive Composite [PACC5], and domain measures of memory and executive function) and brain MRI measures of: macrostructure (volume of gray matter [GM] and WMH from T1‐weighted and FLAIR imaging), white matter microstructure (neurite orientation dispersion and density imaging [NODDI] free water [FW] and diffusion tensor imaging [DTI] fractional anisotropy [FA]), and cerebral blood flow (CBF) in white matter (WM) and GM. Age, race, gender, education, and APOE‐4 status were included as covariates and in interaction terms in linear regression analyses.ResultAmong 458 participants with a mean age 70±8 years and cognitive adjudication (44 dementia, 157 MCI, 257 normal cognition; Table 1), higher cfPWV was associated with worse cognitive performance (MoCA, PACC5), as was SBP (MoCA, PACC5, executive domain, language domain; Table 2). Higher cfPWV was associated with differences in WM microstructure (higher FW, lower FA) and higher WMH volume. While no overall associations between cfPWV and CBF were detected, cfPWV had stronger associations with FW, FA, and WMH in men. Higher SBP was associated with higher FW, higher WMH volume, and lower WM and GM CBF (Table 3). SBP had stronger associations with WMH in younger participants (<70y) and GM CBF in Black/AA participants and participants with impaired fasting glucose. No other interactions were detected.ConclusionsArterial stiffness is associated with microstructural and macrostructural differences and poorer global and executive cognitive function.