bluuebunny/crossref_metadata_2025_split huggingface dataset:
Putative Cellular Identity of Dystrophic Neurites in FTLD‐TDP Type C
Authors: Kawles Allegra , Minogue Grace , Keszycki Rachel M , Zouridakis Antonia , Macomber Alyssa , Weintraub Sandra , Rogalski Emily J , Castellani Rudolph J , Mesulam Marsel , Geula Changiz , Gefen Tamar 
Published: December 2023

AbstractBackgroundApproximately 90% of individuals diagnosed with the clinical syndrome of semantic variant of primary progressive aphasia (PPA‐S) will present at autopsy with the TDP‐43 type C pathologic form of frontotemporal lobar degeneration (FTLD‐TDP‐C). FTLD‐TDP‐C is primarily characterized by the presence of TDP‐43‐immunoreactive long, thick dystrophic neurites (DNs), which tend to be found in superficial cortical layers, perpendicular to the cortical surface. The cellular identity of long DNs is not yet known. This study aims to understand the neuronal origin of DNs via colocalization of pathologic TDP with axonal and dendritic markers.MethodTwo right‐handed cases with FTLD‐TDP‐C as the sole pathologic diagnosis and a clinical diagnosis of PPA‐S were identified from the Northwestern University Alzheimer’s Disease Research Center (NU‐ADRC) brain bank. Participants were co‐enrolled in the NU PPA program, a longitudinal study of individuals with this dementia syndrome. Paraffin‐embedded sections of right inferior frontal gyrus (IFG) were fluorescently double‐stained immunohistochemically with an antibody to TDP‐43 phosphorylated at Ser 409 / 410 (pTDP) and antibodies to either phosphorylated neurofilament (pNFH) or non‐phosphorylated neurofilament (npNFH) to visualize axons or proximal dendrites, respectively. A digital image of each slide was obtained at 20X magnification using the Olympus VS200 Slide Scanner and analyzed using QuPath software (v.0.4.3).ResultIn both cases, staining revealed that a small amount (∼2%) of total DNs per section colocalize with npNFH (see Figure 1). Both long and short DNs, the latter of which are commonly apparent in other pathologic TDP subtypes (e.g., type A), demonstrated colocalization. By observation, half of colocalized DNs were oriented vertically. No DNs were found to colocalize with pNFH.ConclusionPreliminary findings suggest that DNs in FTLD‐TDP‐C may be remnants of dystrophic dendrites. The vertical orientation of colocalized DNs could reflect the orientation of apical dendrites in superficial layers of cortex. It is possible that DNs that did not colocalize with dendritic or axonal protein may be of distal dendritic origin or may reflect loss of dendritic protein in affected neurons. While it is difficult to determine the pathogenic history of DNs, these observations are promising and warrant future in‐depth investigation.
Association of Exercise Types in Adolescence with Cognitive Function in Older Age: the Bunkyo Health Study
Authors: Shi Huicong , Tabata Hiroki , Otsuka Hikaru , Someya Yuki , Kaga Hideyoshi , Naito Hitoshi , Abulaiti Abudurezake , Kiya Mai , Ito Naoaki , Tajima Tsubasa , Yoshizawa Yasuyo , Kakehi Saori , Kawamori Ryuzo , Tamura Yoshifumi 
Published: December 2023

AbstractBackgroundExercise in adolescence has been shown to increase cognitive reserve and have a long‐term preventive effect on cognitive function in older age (Dik, M. G., et al. 2003). However, it remains unclear whether different types and intensities of adolescent exercise have distinct impacts on cognitive function later in life. Therefore, the present study investigated the association between exercise types and intensity in adolescence and mild cognitive impairments (MCI) in older adults.MethodWe analyzed data from the Bunkyo Health Study, which included 659 men and 912 women aged 65‐84. MCI was defined as the Japanese version of the Montreal Cognitive Assessment score of 22 points or less. We classified the 35 exercises participants engaged in their junior high school and high school reference to the classification guidelines (Maron, B. J., et al. 2015), which were divided into three levels of exercise intensity (low, moderate, high) in each type of exercise (aerobic, resistance, or a combination of both). Multivariate‐adjusted logistic regression models were used to estimate the odds ratios (ORs) and associated 95% confidence intervals (CIs) in each category level for the prevalence of MCI, as compared with the non‐exercise group.ResultIn junior high school analysis, the ORs(95%CIs) for MCI were significantly lower in the moderate‐resistance level group (OR: 0.45 [0.21‐0.95], P‐value = 0.04) and the high‐combination level group (OR: 0.30 [0.11‐0.81], P‐value = 0.02) in men, whereas there were no significant differences in women. Similar results were observed in high school analysis, with lower ORs for MCI in moderate‐resistance level (OR: 0.36 [0.16‐0.77], P‐value = 0.01) and high‐combination level (OR: 0.34 [0.14‐0.80], P‐value = 0.01) groups, but not for women.ConclusionParticipation in the moderate‐resistance level and/or the high‐combination level exercises in junior high school or high school was associated with a lower prevalence of MCI in older age among men, but not women.
Implementation of amyloid PET in a memory clinic of geriatric hospital revealed characteristics of causative diseases by age
Authors: Ishii Kenji , Ishibashi Kenji , Sakata Muneyuki , Kamitaka Yuto , Tago Tetsuro , Kanemaru Kazutomi , Murayama Shigeo , Iwata Atsushi , Toyohara Jun 
Published: December 2023

AbstractBackgroundClinical impact and significance of amyloid PET on dementia diagnosis in the real‐world memory clinic of gerontology hospital have been evaluated by age group.MethodsWe analyze the data from 340 adult patients (age 72.3 ± 9.9, M/F: 151/189) visited the memory clinic of Tokyo Metropolitan Institute for Geriatrics and Gerontology with progressive cognitive decline and who had PiB‐PET for clinical evaluation. Pre‐PET diagnosis was based on the clinical evaluation with neuropsychological tests, MRI for all the cases and with perfusion SPECT, dopamine transporter SPECT, MIBG cardiac scintigraphy as needed. PiB‐PET was evaluated by visual diagnosis (A+/A‐). FDG‐PET was added for further differentiation. Post‐PET diagnosis was analyzed 3 to 6 months after PiB‐PET in three age groups (age<65, 65‐74, and > = 75). We obtained autopsy diagnosis from 25 cases of them.ResultsWe included 189 females and 151 males (age 72.3 ± 9.9). Pre‐PET diagnosis consisted of 198 AD and 142 non‐AD. 27% of clinically diagnosed AD patients were considered non‐AD by PiB‐PET. 30% of clinically diagnosed non‐AD patients were amyloid positive, one third of them were reconsidered to be AD, however, two‐thirds of them were still regarded as non‐AD (concomitant pathology) especially in the aged patients. Amyloid positivity more strongly suggest AD in younger patients. Younger patients have larger population of non‐pathological background such as depression, adjustment disorder, developmental disorder, etc. Autopsy diagnosis confirmed the accuracy of PiB‐PET diagnosis.ConclusionPiB‐PET provides highly accurate diagnosis of dementia which has age‐related characteristics.
CSF markers YKL40, sTREM2, and a‐synuclein enhance the Alzheimer’s disease A/T/N criteria to detect early changes in cognition
Authors: Canovas Rodrigo , Fowler Christopher J , Li Qiao‐Xin , Rainey‐Smith Stephanie R , Carboni Margherita , Suridjan Ivonne , Kollmorgen Gwendlyn , Logan Chad , Collins Steven J , Maruff Paul , Martins Ralph N , Fripp Jurgen , Zetterberg Henrik , Blennow Kaj , Masters Colin L , Doecke James D ,   the AIBL Research Group
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial disease including pre‐clinical, prodromal and clinical phases. CSF “A/T/N” (Ab42, pTau181, tTau) biomarkers help characterize the biological state of AD. The primary aim was to assess contributions of eight CSF markers for predicting changes in cognition.MethodCSF from 237 participants (CN: 176[74.3%], MCI: 33[13.9%], AD: 28[11.8%]) of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing was used to measure Ab42 (GenII assay), pTau181, and tTau (Elecsys®) along with neurogranin, neurofilament light (NFL), α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells‐2 (sTREM2), s100 calcium‐binding protein B (s100B), and interleukin‐6 (IL‐6) from the NeuroToolKit (NTK) panel of exploratory prototype assays (all Roche Diagnostics International Ltd). NTK biomarker concentrations were measured amongst each of four ATN groups at baseline; 1) A‐/T‐/N‐ (reference group), 2) A+/T±/N± (amyloid+), 3) A‐/T±/N± (amyloid‐), and 4) A+/T+/N+. Change in cognition was assessed using the pre‐clinical Alzheimer’s cognitive composite (PACC) and the clinical dementia rating sum of boxes (CDR‐SB) scores, in all four ATN groups, stratified by low/high NTK biomarker over a minimum of 36 months. The primary outcome was defined as change in cognition in amyloid+ participants modulated by the addition of NTK markers to ATN groups.ResultA+/T+/N+ participants had faster cognitive decline on both PACC and CDR‐SB over time compared to all other groups (Figure 1A, PACC; Figure 1B, CDR‐SB). Within the amyloid+ group, participants with high sTREM2 (K+) had a faster rate of decline in PACC compared to those with low sTREM2 (K‐, p = 0.04; Figure 1C), whilst participants with high α‐synuclein had a faster increase in CDR‐SB compared with those with low α‐synuclein (p = 0.005; Figure 1D). Amongst participants who were A+/T+/N+, those with high YKL40 had a significantly faster rate of decline in PACC (p = 0.017; Figure 1E), and a faster increase in CDR‐SB, (p = 0.017; Figure 1F) compared with those who with low YKL40.ConclusionBiomarkers of microglial activation (sTREM2), synaptic function and synuclein metabolism (α‐synuclein), and astrocytic activation (YKL‐40) may be appropriate to discern rates of cognitive change within amyloid+ participants. Findings are being validated in a separate population.
Association of the learning ratio with AD biomarkers after application of actuarial diagnostic criteria to ADNI cognitively normal participants
Authors: Pentchev Julian V. , Kim Hee Jin , Polsinelli Angelina J , Apostolova Liana G. , Hammers Dustin B. 
Published: December 2023

AbstractBackgroundEarly and accurate diagnosis is critical as disease‐modifying therapies for Alzheimer’s disease (AD) become available and clinical trials are moving increasingly into early disease stages. The Learning ratio (LR) has demonstrated the highest sensitivity towards changes in memory, relative to other learning slope metrics. The current study examines the performance of LR within the ADNI cognitively normal population.MethodOur analyses included 672 participants aged 55 to 90 years, diagnosed in ADNI as cognitively intact. After applying Jak/Bondi actuarial diagnostic criteria to the sample1, 2, 56 participants met actuarial criteria for MCI (actuarial‐MCI), 253 had normal cognition with subjective memory complaints (actuarial‐SMC), and 363 were cognitively normal without subjective complaints (actuarial‐CN). We compared LR derived from the Rey Auditory Verbal Learning Test (RAVLT)3 and the Word Recall subtest of the ADAS‐Cog4 between the diagnostic groups, and studied the effects of LR, diagnosis, and the interaction between LR and diagnosis on bilateral hippocampal volume and β‐amyloid pathology.ResultActuarial‐MCI performances on RAVLT LR and Word Recall LR were significantly worse than actuarial‐SMC and actuarial‐CN (ps<.005). No differences were seen between LRs for actuarial‐CN and actuarial‐SMC (ps>.05). The association between Word Recall LR and hippocampal volume was strongest in actuarial‐MCI followed by actuarial‐SMC, both of which displayed a positive relationship between the two variables, while actuarial‐CN displayed a negative relationship (R2
= .209, p<.001, Figure 1A). Adding the interaction term improved model performance (R2 change = .007 p = .013). Similar trends were observed between RAVLT LR and diagnostic group predicting hippocampal volume, though the interaction was not significant (R2 = .208, p<.001, Figure 1B; R2 change = .001 p = .28). No main or interaction effects were observed between LR measures, diagnostic groups, and amyloid status (ps>.05, Figure 2).ConclusionA subset of ADNI cognitively intact participants displayed MCI after applying Jak/Bondi actuarial norms, suggesting that ADNI diagnostic criteria may have under‐pathologized memory loss in a subset of patients. The actuarial‐MCI group displayed worse learning slopes and stronger relationships with hippocampal volume than CN participants with and without SMC. Applying the actuarial criteria to AD clinical trials – in conjunction with LR – may yield greater sensitivity in detecting those in the early stages of AD.
Visual versus quantitative assessments using Pittsburgh compound‐B and Flutemetamol PET scans across age groups
Authors: Zeydan Burcu , Johnson Derek R. , Schwarz Christopher G. , Lee Jeyeon , Przybelski Scott A. , Lesnick Timothy G. , Senjem Matthew L. , Kantarci Orhun H. , Min Paul H , Kemp Bradley J. , Jack Clifford R. , Kantarci Kejal , Lowe Val J. 
Published: December 2023

AbstractBackgroundBoth 11C‐Pittsburgh compound‐B (PiB) and 18F‐Flutemetamol (FMT) have off‐target white matter (WM) signal that increases with age, but WM uptake is stronger with FMT than PiB. Although their WM patterns are comparably associated with age, the difference between them may impact visual and quantitative assessments of cortical amyloid‐β uptake. Our objective was to determine whether PiB PET and FMT PET visual assessments agree with quantitative cortical amyloid‐β evaluations.MethodA cohort of cognitively unimpaired (CU) younger adults with median (range) of 39 (30, 48) years (N = 30), CU older adults with age of 67 (61, 83) years (N = 30) and older adults with AD dementia with age of 67 (54‐84) years (N = 23) underwent MRI, PiB PET and FMT PET. PiB‐PET and FMT PET scans were evaluated visually by two nuclear medicine specialists blinded to participant information. Disagreements were reconciled with a second, joint round of visual reads. Readers applied standard visual assessment criteria using the absence of regional gray matter (GM) and WM contrast as an indication of a positive scan. The global cortical PiB standard uptake value ratio (SUVr) was obtained referencing to cerebellar crus uptake and converted to centiloid values. Participants were classified as PiB positive/negative using a centiloid cut‐off of 22.ResultPiB and FMT visual positivity agreed with quantitative positivity on PiB‐based centiloid values in 69/83 for PiB and 78/83 for FMT. There were 10 disagreements with PiB, 1 disagreement with FMT and 4 disagreements with both. Few disagreements occurred near the centiloid threshold. Interestingly, all disagreements between visual reads (amyloid‐β positive) and centiloid (amyloid‐β negative) in the CU younger were with PiB. FMT disagreements were always in the CU older and AD groups.ConclusionDisagreements between amyloid‐β positivity on visual reads and quantitative measurements (centiloid) may depend on age and tracer. PiB WM uptake is lower than FMT WM uptake, which may lead to reduced contrast between GM and WM (part of the standard criteria for visual reads), especially in younger ages. In contrast, WM uptake increases at older ages, and increased WM signal may bleed more into cortical regions, hiding subtle, near‐threshold cortical uptake, especially with FMT.
Relationship between generalization performance and plasma markers pTau231, pTau181 and NfL in cognitively healthy older African Americans
Authors: Osiecka Zuzanna , Sheikh Mustafa , Budak Miray , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Fausto Bernadette A. , Gluck Mark A. 
Published: December 2023

AbstractBackgroundPhosphorylated tau (pTau) in cerebrospinal fluid (CSF) is a biomarker of Alzheimer’s disease (AD) pathology. Recent studies confirm that pTau levels in plasma may provide a more cost‐effective and less invasive method of assessing AD pathology, which have shown to also be relevant in preclinical populations. Neurofilament light (NfL) is a measure of neuroaxonal damage associated with poorer cognitive outcomes. Generalization is a validated cognitive marker of hippocampal dysfunction, with individuals showing deficits years before overt cognitive impairment. Using a computer generalization task sensitive to medial temporal lobe (MTL) pathology, the current study examined the relationship between generalization performance and plasma pTau and NfL levels in a population with elevated AD risk, older African Americans.Method130 older, cognitively normal African Americans (M
age = 71.60 years, SD = 6.58; M
edu = 13.88 years, SD = 2.37; n = 98 women) provided blood samples and completed a hippocampal‐dependent cognitive task. Participants’ normal cognitive status was confirmed using the Mini‐Mental State Examination (M
MMSE = 26.98, SD = 2.14) and generalization performance was assessed using the Acquired Equivalence Task. Plasma was extracted from blood samples to assess pTau181, pTau231, and NfL levels. Based on the sample median thresholds, participants were characterized as plasma tau positive (≥16.189 for pTau181 and ≥17.537 for pTau231).ResultParticipants positive for plasma pTau231 (n = 76) demonstrated worse generalization performance with increased pTau231 levels, B = ‐0.296, p = 0.024, as did participants positive for plasma pTau181, B = ‐0.247. p = 0.042, demonstrating that tau positivity status is related to MTL dysfunction. Moreover, pTau231 was more strongly associated with generalization performance, indicating that it is a more sensitive biomarker than pTau181 among preclinical AD populations. Higher levels of plasma NfL were also significantly associated with lower generalization performance B = ‐0.243. p = 0.008.ConclusionPlasma isoforms pTau181 and pTau231 may reflect different phases of tau progression, with plasma pTau231 shown to be better at capturing subtle MTL dysfunction. Plasma tau positivity status and measures of axonal damage along with lower generalization performance scores may be useful indicators of cognitive dysfunction in preclinical AD populations.
A brain penetrant small‐molecule SYK inhibitor for the treatment of Alzheimer’s and neuroinflammatory diseases
Authors: Stuchbury Grant , Ko Angela , Dymock Brian 
Published: December 2023

AbstractBackgroundSpleen tyrosine kinase (Syk) is a cytosolic pro‐inflammatory signalling kinase that is associated with several neuroinflammatory conditions, including Alzheimer’s disease. We have developed structurally novel QED‐701, a brain‐penetrant, small molecule inhibitor of Syk that possesses excellent pharmacokinetic properties and displays anti‐inflammatory efficacy in vivo.MethodQED‐701 was administered to 5xFAD mice for 4‐months, beginning at 8‐weeks of age. At termination, the pro‐inflammatory profile in the brain was assessed by qPCR and histology was performed for amyloid, neuron health and microglial activation.ResultQED‐701 significantly reduced inflammation in the brain of 5xFAD mice, in a dose‐dependent manner that correlates to Syk inhibition in the CNS.ConclusionQED‐701 is a preclinical candidate for the treatment of Alzheimer’s disease and other neuroinflammatory conditions. It is a potent and selective inhibitor of Syk that readily enters the brain and displays anti‐inflammatory efficacy in the 5xFAD model of Alzheimer’s disease.
CSF Fraction Mapping Derived from Multi‐echo MR FAST‐T2 Sequence Could be an Alternative Measure of Total Perivascular Space in the Brain Parenchyma
Authors: Zhou Liangdong , Nguyen Thanh D , Wang Xiuyuan Hugh , Tanzi Emily , Xi Ke , Chiang Gloria , de Leon Mony J. , Li Yi 
Published: December 2023

AbstractBackgroundPerivascular space (PVS), as the key pathway of the glymphatic clearance, has been studied from various aspects. The volume of PVS is considered a biomarker of the enlargement of PVS, which may reflect the deficits of the clearance function. However, most of the methods for the estimation of PVS depends on the segmentation of visible PVS on anatomical MRI, which inherently ignored the invisible PVS that are of sub‐voxel size and dominant of the total PVS. We proposed a muti‐echo T2 relaxometry based CSF water fraction (CSFF) mapping method using 3‐water compartment model. The CSFF mapping corresponding to the long T2 (>200 ms) compartment in the total signal fitted using a 6 echo FAST‐T2 data.MethodForty‐one subjects were recruited (Age: 58.5±17.0, 25 normal (NL), 16 Aβ+ MCI/AD) including 26 females and 15 males. CSFF was reconstructed from the 6 echo FASTT2 data by fitting a three‐water compartment model. PVS in cerebral white matter was segmented using the Frangi filter on the enhanced PVS image. Intracranial volume was segmented using SPM12 for the PVS load normalization.ResultFigure 1 shows the distribution of CSFF and PVS by groups. There is significant difference of CSFF between NL and MCI/AD groups, and no difference of PVS between groups. Figure 2 shows the linear relationship between GM CSFF and normalized PVS load. We see CSFF is about 10 times larger than PVS load. We know the CBV is about 3∼5% of the whole brain. CSFF value is about the same level of CBF, which is very reasonable. It also shows that CSFF has better ability to distinguish NL and MCI/AD than PVS load. Figure 3 shows the high consistency between the CSFF from both high and low resolution FASTT2 data. High resolution CSFF has less partial volume effect, that’s why it has about 0.5% higher value than the low resolution CSFF.ConclusionThe CSF fraction (CSFF) mapping is useful to detect early changes in AD, which may reflect the subtle changes of total PVS space in the brain.
Acknowledgement: This study is supported by NIA grant AG057848