bluuebunny/crossref_metadata_2025 huggingface dataset:
Recruitment strategies and tactics for INTERCEPT‐AD: A phase I trial of Aβ oligomer‐targeting ACU193 in early Alzheimer’s disease
Authors: Moxon Robyn , Feaster Todd , Carroll Alyssa , Gan Siew Tin , Ziemba Shane , Price Kimber , Skljarevski Vladimir , Sundell Karen L , Sethuraman Gopalan , Hitchcock Janice , Siemers Eric R
Published: December 2023

Background

Clinical trials are essential for testing safety and efficacy of potential treatments for Alzheimer’s disease (AD), but recruitment is often difficult due to a variety of factors. Recruitment tactics in AD clinical trials may include media advertising, physician referrals, patient registries, and referral campaigns. Newer strategies such as social media and community outreach have also been successful in increasing recruitment. However, not all recruitment tactics are successful for every study site and a multi‐faceted approach tailored to each site may be more successful.

Method

INTERCEPT‐AD is a phase 1 randomized, double‐blind study of ACU193 in mild cognitive impairment or mild dementia due to AD. Seventeen study sites in the U.S. screened potential participants identified through multiple recruitment tactics which were grouped post hoc into seven categories: site database, external referral, physician referral, site campaign, and three sponsor‐initiated campaigns. Recruitment efforts were tailored to each site’s patient population, community, and staff availability.

Result

INTERCEPT‐AD screened 260 participants and 70 were eligible for study participation. Recruitment was completed in January 2023. The sponsor worked directly with individual sites to develop a tailored recruitment plan that considered each site’s target population, historically successful recruitment tactics, and current ability to screen patients from outside sources. Comparisons of the seven types of recruitment sources showed site databases were used most frequently (12/17 sites, 71%) and accounted for the most screenings and eligible participants (107 [41%] and 32 [46%], respectively). Additional data from all recruitment sources and success rates will be presented.

Conclusion

Study sites found success using a combination of tactics specifically tailored to their enrollment goals. Sites with robust internal patient databases had higher rates of screening and enrollment. A combination of site‐led and sponsor‐driven recruitment initiatives likely maximized enrollment rates. These findings suggest a strategy using diverse recruitment tactics customized to a study site’s capabilities and patient population may be more successful than a one‐size‐fits‐all approach.
Age‐related and AD pathology‐related differences in neural activation and neural specificity in memory
Authors: Chen Xi , Varghese Leah , Baker Suzanne L. , Jagust William J.
Published: December 2023

Background

Beta‐amyloid (Aß) and tau deposition is spatially selective in the early stages of Alzheimer’s Disease (AD), with Aß depositing predominately in posterior‐medial (PM) regions and tau accumulating in the medial temporal lobe (MTL) with increasing age before spreading to anterior‐temporal (AT) regions. Functionally, AT and PM are linked to object and scene processing, respectively, and the hippocampus in the MTL is important for integration and forming associations between objects and scenes. Given the differential vulnerability of AT, PM, and MTL to Aß and tau, we examined the behavioral and neural differences in memory for objects, scenes, and object‐in‐scene pairs between young and cognitively normal older adults with and without AD pathologies.

Method

Twenty‐three young (19‐34 yrs) and 32 older (60‐91 yrs) participants completed an incidental encoding task on object, scene, and object‐in‐scene pair images during fMRI and a recognition test outside the scanner (Fig.1). Thirty older participants underwent PiB and FTP PET that measured Aß and tau. We conducted univariate whole‐brain analysis and multi‐voxel pattern analysis (MVPA) of AT, PM, and the hippocampus. The MVPA trains a support vector machine to classify the stimulus category (object, scene, pair) based on the ROI’s activation pattern. A higher classification accuracy represents informative neural representation that reflects functional specificity of the region.

Result

Behaviorally, older people had worse object (ps<.027) and pair (ps<.017) memory. Greater temporal meta‐ROI tau was related to worse object (p = .032) and pair (p = .022) memory. Whole‐brain analyses showed activations in AT and PM networks for object and scene processing, and additional frontal, temporal, and occipital regions for pair processing (Fig.2A‐C) where older adults, compared to younger adults, showed activation reductions in fusiform, parahippocampal, precuneus, and occipital regions (Fig.2D). The MVPA revealed age‐related reductions in classification accuracy for pairs (Fig.3A) and that greater Aß and tau were related to lower accuracy in the hippocampus (Fig.3B).

Conclusion

We found evidence supporting specific vulnerabilities in object and associative memory in older adults correlated with tau pathology. FMRI findings suggest both lower neural activation and lower neural specificity in older adults when processing complex associations. AD pathology appears to contribute to lower neural specificity in the hippocampus.
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

Background

Approximately 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.

Method

Two 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).

Result

In 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.

Conclusion

Preliminary 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

Background

Exercise 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.

Method

We 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.

Result

In 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.

Conclusion

Participation 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

Background

Clinical impact and significance of amyloid PET on dementia diagnosis in the real‐world memory clinic of gerontology hospital have been evaluated by age group.

Methods

We 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.

Results

We 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.

Conclusion

PiB‐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

Background

Alzheimer’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.

Method

CSF 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.

Result

A+/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.

Conclusion

Biomarkers 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

Background

Early 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.

Method

Our 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.

Result

Actuarial‐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).

Conclusion

A 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

Background

Both 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.

Method

A 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.

Result

PiB 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.

Conclusion

Disagreements 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

Background

Phosphorylated 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.

Method

130 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).

Result

Participants 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.

Conclusion

Plasma 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

Background

Spleen 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.

Method

QED‐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.

Result

QED‐701 significantly reduced inflammation in the brain of 5xFAD mice, in a dose‐dependent manner that correlates to Syk inhibition in the CNS.

Conclusion

QED‐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

Background

Perivascular 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.

Method

Forty‐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.

Result

Figure 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.

Conclusion

The 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
Quantitative Transport Mapping Derived Tracer Velocity for Alzheimer’s Disease
Authors: Zhou Liangdong , Wang Yi , Chiang Gloria , de Leon Mony J. , Li Yi
Published: December 2023

Background

The Alzheimer’s disease (AD), featured with extracellular beta‐amyloid plaque and intracellular tau tangles, are considered caused by the brain clearance function deficits. One anatomical representation of the fluid stasis is the enlargement of the perivascular space. Our hypothesis is that the fluid stasis will reduce the fluid velocity, and the reduced fluid velocity will drive the PET tracer slower than normal. We used the velocity map from our proposed quantitative transport mapping (QTM, L. Zhou MRM 2020.) to evaluate the PET tracer velocity in Alzheimer’s disease.

Method

Fifty‐seven subjects (age: 69.7±9.1, Female/male = 37/20, NL/MCI = 45/12) went through both 11C‐PIB and 18F‐MK‐6240 PET scan for Aβ and tau deposit measurements, and MRI scan for ROI parcellation. PIB SUVR, MK vCSF‐Slope (Y. Li Fluids Barriers CNS 2022), MK QTM are processed for the following analysis. Specifically, vCSF‐Slope was computed as the tracer turnover rate in lateral ventricle using the dynamic MK data between 10 to 30min, normalized by the whole brain AUC in 1 to 4min. QTM velocity was processed using the dynamic MK data between 40 to 55min using mass conservation equation. Regression model for predicting Aβ using QTM was conducted by controlling for age and sex. The relationship between QTM and vCSF was evaluated. The use of QTM to distinguish subjects groups are tested.

Result

Our preliminary results showed that quantitative transport mapping(QTM) based on fluid mechanics is significantly associate the ventricular CSF clearance(vCSF) measured by dynamic PET data and brain amyloid(PiB PET). The regression model shows that cerebral cortex (GM) QTM velocity (p<0.01, t = ‐2.76) and age (p<0.05, t = 2.55) are significantly associated with the GM PIB SUVR as shown in Figure 1. This indicates that high Aβ deposit is associated with lower QTM velocity, i.e., clearance deficits. Figure 2 shows that in GM QTM velocity is correlated with the vCSF‐Slope (p<0.05, r = 0.37). Figure 3 shows that QTM velocity in both GM and lateral ventricle are able to distinguish normal and MCI/AD groups.

Conclusion

The tracer velocity in the brain tissue measured by QTM is associated with ventricular CSF turnover rate and brain amyloid burden.

Acknowledgement: This study is supported by NIA grant AG057848
Blood‐based quantification of Aβ oligomers indicates impaired clearance from brain in ApoE ε4 positive subjects
Authors: Willbold Dieter , Blömeke Lara , Rehn Fabian , Pils Marlene , Kraemer‐Schulien Victoria , Kutzsche Janine , Bujnicki Tuyen , Priller Josef , Schneider Anja , Wiltfang Jens , Jessen Frank , Düzel Emrah , Bürger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Wagner Michael , Peters Oliver , Bannach Oliver
Published: December 2023

Background

Quantification of Aβ oligomers in plasma may be useful not only for early diagnosis of Alzheimer’s disease (AD), but particularly to improve our understanding of underlying pathologies. However, quantification necessitates an extremely sensitive and selective technology due to very low concentrations and possible interferences of matrix components. Owing to their central role in AD pathology, oligomers are an attractive therapeutic target to ultimately halt disease progression or even to cure AD.

Method

In the present study, we developed and validated the surface‐based intensity‐distribution analysis (sFIDA) assay for quantification of Aβ oligomers in plasma. sFIDA is single particle sensitive and completely insensitive to Aβ monomers.

Result

The blood‐based sFIDA assay delivered a sensitivity of 1.8 fM, an inter‐ and intra‐assay variation below 20% for silica‐nanoparticles (SiNaPs) as calibration standard, and no interference with matrix components. Quantification of Aβ oligomers in 366 plasma samples from the DELCODE cohort, revealed decreased oligomer concentrations in subjective cognitive decline and AD patients compared to healthy controls. Correlation analysis between CSF and plasma oligomer concentrations suggest an impaired clearance of Aβ oligomers depending on ApoE ε4 status.

Conclusion

sFIDA is able to quantitate Aβ oligomers in plasma samples down to the low fM range. Aβ oligomers in plasma may reveal clearance mechanisms from the brain into blood, and how they are impaired during disease progression.
Concurrent MR‐PET investigation of memory consolidation and dopaminergic modulation in ageing
Authors: Yi Yeo‐Jin , Garcia‐Garcia Berta , Johansson Jarkko , Betts Matthew , Speck Oliver , Kreißl Michael C. , Düzel Emrah , Hämmerer Dorothea
Published: December 2023

Background

The dopaminergic system plays a crucial role in modulating learning and memory and undergoes age‐related changes that contribute to neurological disorders (Volkow et al., 1998; Pan et al., 2019) and reduced cognitive maintenance in ageing (Nyberg et al., 2016). Advanced imaging techniques can assess dopaminergic function in vivo in humans. In our study, we used dynamic concurrent magnetic resonance‐positron emission tomography (MR‐PET) which allows to infer dopamine release concurrent to functional MR imaging to investigate the relationship between dopaminergic neuromodulation in memory and healthy ageing. These measurements provide valuable insights into the critical role of the dopaminergic system in sustaining cognitive function during ageing and may help us elucidate the consequences of neuromodulatory decline in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s dementia.

Method

27 healthy adults over 65 underwent two dynamic MR‐PET imaging sessions with [18F]fallypride to measure D2/3 receptor occupancy and changes in nondisplaceable binding potential (∆BPND) in the striatum and extrastriatal regions. MRI scans were acquired concurrently, along with functional scans during a reward‐based memory task. Transient endogenous dopamine release was captured using a linear parametric neurotransmitter PET model.

Result

∆BPND of active PET (high dopamine condition) session was negatively correlated with the T‐static values in the bilateral hippocampus activation clusters in the reward versus neutral scene stimuli contrast (rho = ‐.41, p<.05), while the correlation was nonsignificant in passive PET (low dopamine condition) session.

Conclusion

We used concurrent MR‐PET imaging to investigate the role of endogenous dopamine release and hemodynamic activity in memory consolidation. Higher endogenous dopamine release in the hippocampus during memory encoding was associated with greater functional activation in response to reward‐associated stimuli. Future analyses will examine links between brain health indicators and individual differences in memory consolidation and cognitive function. These findings may have implications for improving memory function in ageing and neurodegenerative diseases.
Human CSF pharmacoproteomics establishes in vivo‐relevant BACE1 substrates as pharmacodynamic biomarkers for chronic BACE inhibition in clinical trials
Authors: Lichtenthaler Stefan F , Giesbertz Pieter , Graf Ana , Kennedy Matthew E. , Horiguchi Naotaka , Müller Stephan A.
Published: December 2023

Background

BACE1 is a major drug target for Alzheimer’s disease, but several late‐stage clinical trials with BACE‐inhibitors were associated with adverse events, most notably worsening in measures of cognitive function. Inhibition of BACE1‐dependent processing of a set of CNS membrane proteins is possibly responsible for these adverse findings. It is however unknown, which physiological BACE1 substrates are affected in humans at clinically relevant doses of a BACE inhibitor. To identify such substrates, we carried out a quantitative proteomic analysis of cerebrospinal fluid (CSF) from a subset of participants of phase 2 clinical trials with umibecestat or atabecestat or of a phase 3 clinical trial with verubecestat.

Method

Pre‐ and post‐dose CSF samples were quantitatively analyzed by nanoLC‐MS/MS. Selected proteins were further validated by ELISA. Changes in BACE1 substrate abundance were correlated with changes in Ab, sAPPb and with occurence of cognitive worsening.

Result

More than 1,000 CSF proteins were relatively quantified between the BACE inhibitor‐treated groups versus placebo. The cleaved extracellular domains of several BACE1 substrates with established neuronal or synaptic functions displayed a dose‐dependent reduction. This included SEZ6, SEZ6L, CACHD1, CHL1, L1 and the APP family members APLP1 and APLP2. While some substrates, e.g. SEZ6, were reduced to similar degree as Ab and sAPPb, the reduction for other substrates was less than 50%, presumably because they are cleaved by additional proteases other than BACE1. BACE inhibition significantly and dose‐dependently increased CSF abundance of only a single quantified protein, the myelin‐associated glycoprotein. Similar protein changes upon BACE inhibition or BACE1 deletion were seen in CSF of mice and of non‐human primates and indicate that BACE1 substrates are evolutionarily conserved.

Conclusion

BACE inhibitors in clinical trials block cleavage of multiple BACE1 substrates in a dose‐dependent manner. A reduction of the inhibitor dose to less than 50% BACE1 inhibition may be an appropriate strategy to avoid side effects in future clinical trials with BACE inhibitors. Our analysis also demonstrates that proteomics enables pharmacodynamic studies of multiple CSF proteins in single measurements, which are suitable for precision medicine approaches in future clinical trials with BACE inhibitors.
Performance of optimized prototype LUMIPULSE G immunoassays for plasma pTau181 and pTau217
Authors: Lambrechts Charlotte , Van Loo Maxime , Vanbrabant Jeroen , Dekeyser Filip , Bayoumy Sherif , Verberk Inge M.W. , Zwan Marissa D. , van der Flier Wiesje M. , Rubel Carrie E. , Czerkowicz Julie , Fraser Kyle , Graham Danielle , Inaoka Daigo , Aoyagi Katsumi , Teunissen Charlotte E. , Stoops Erik
Published: December 2023

Background

There is a need for automated random access plasma phosphorylated Tau (pTau) methods that reflect AD pathology with consistent performance. LUMIPULSE (LP) assays could offer a solution. Initial prototype pTau181 and pTau217 LP assays showed lower clinical performance versus Quanterix Homebrew assays (Poster #79533 – P4‐06). This new study presents optimized pTau181 and pTau217 LP assays, showing data on their analytical and clinical performance compared to the initial prototype method (Ref) and an in‐house pTau181 Quanterix Homebrew assay.

Method

Plasma pTau181 and pTau217 LP assays were developed using recombinant pTau181 mAb RD‐070, resp. pTau217 mAb RD‐085, combined with an ALP‐Fab conjugate from recombinant N‐terminal Tau mAb RD‐073. In the optimized automated protocol, an assay specific diluent (ASD) is added (20%) to the sample to increase signal specificity. Analytical and clinical performance of the reference versus ASD‐treated prototypes to distinguish AD from controls was evaluated using 40 CSF‐confirmed AD‐dementia and 40 age‐matched healthy volunteer plasma samples.

Result

Analytical performance: Both optimized pTau181 and pTau217 LP tests demonstrated high precision comparable to their reference assays (inter‐run %CV on 3 neat plasma samples < 7.4). LLOQ was not affected by ASD‐treatment. Clinical performance: pTau181 LP assays demonstrated comparable AUC and median fold change with (AUC 0.828, fold change 1.9) and without ASD (AUC 0.823, fold change 1.5) while the SIMOA assay demonstrated a higher AUC (0.866) and fold change (2.9). For pTau217, the performance improved from an initial AUC of 0.918 to 0.935, and a fold change of 3.72 instead of initially 2.76. (Figure 1). All assays correlated strongly (p<0.00001) (Table 1); highest correlations among them were observed with the pTau217 ASD‐treated assay.

Conclusion

Using an assay specific diluent resulted in improved clinical performance for the pTau217 prototype LUMIPULSE assay, in line with other published pTau217 assays. We did not achieve improved performance of the pTau181 LP assay with the ASD addition. Most important to emphasize, a performant pTau217 assay prototype is under development on an fully automated, scalable platform. Next steps include verification of performance in additional well‐characterized AD cohorts and characterization of lot consistency and robustness of the pTau181 and pTau217 N‐terminal LUMIPULSE assays.
The effect of oral galactose on oxidative stress in the brain of a transgenic mice model of Alzheimer’s disease
Authors: Barilar Jelena Osmanović , Kovac Diana , Knezovic Ana , Perhoc Ana Babic , Salkovic‐Petrisic Melita
Published: December 2023

Background

Changes in the brain energy metabolism and oxidative stress can be found before development of Aβ plaques in Alzheimer’s disease (AD) and galactose showed potential therapeutic effect in Tg2576 mice AD model. We aimed to investigate changes in the hippocampal (HPC) energy status and oxidative stress before and after galactose treatment in this model.

Method

Adult male B6; SJL‐Tg(APPSWE)2576Kha transgenic (TG) mice (Tg2576) and wild types (WT) aged 5 (5M) and 10 (10M) months were used. Oral galactose therapy was given to half of WT (WT+G) and half of TG (TG+G) group for 2 months (200mg/kg/day), while another half of each group received water ad libitum. Protein expression of insulin receptor substrate (total and phosphorylated; IRS, pIRS), AMP‐activated protein kinase (AMPK, p‐AMPK) was measured by western blot. Corticosterone levels were measured by ELISA, and spectrophotometry were used to measure the parameters of oxidative stress (MnSOD; TBARS). Data were analyzed by Kruskal‐Wallis and Mann‐Whitney U‐test (p<0.05).

Result

The levels of corticosterone were decreased in 5M TG mice (p = 0.0055; n = 8) and galactose (5M TG+G) increased it to the levels of control. Galactose decreased MnSOD (p = 0.0329;n = 5) in 10M TG mice. The decrement in p/t IRS ratio (p = 0.043; n = 5) was seen only in 10M TG mice, and galactose (10M TG+G) reversed it to the levels of control. Increased AMPAK levels were found in 5M TG+G (p = 6,5e‐04; n = 5) and 5M WT+G (p = 8,6e‐05; n = 5) groups, while pAMPK was increased only in 5M TG (p = 0.013; n = 5), and decreased in 5M TG+G group after galactose treatment (p = 0.034: n = 5).

Conclusion

Galactose increased the corticosterone and AMPK levels in young TG mice, while in older TG mice oral galactose had the effect on the level of MnSOD and p/t IRS ratio. The potential therapeutic impact of oral galactose in Tg2576 mice seems to be connected to maintaining of oxidative stress and energy balance and depends on the animal age and AD stage at which the treatment was initiated. Supported by HRZZ IP‐2018‐01‐8938 and the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic‐ischemic damage in perinatal and adult brain”, GA KK01.1.1.01.0007 funded by the European Union)
Effects of a 24‐week resistance exercise program on psychological distress in cognitively normal older adults. Preliminary results of The AGUEDA Randomized Control Trial
Authors: Bellon Dario , Rodriguez‐Ayllon Maria , Solis‐Urra Patricio , Coca‐Pulido Andrea , Mora‐Gonzalez Jose , Toval Angel , Fernández‐Ortega Javier , Bakker Esmée A , Ortega Francisco B , Esteban‐Cornejo Irene
Published: December 2023

Background

The World Health Organization (WHO) estimates that, by 2050, the world’s population over the age of 65 will reach 71 million, and in turn, there is a clear trend of increasing numbers of older adults with some form of mental illness. Indeed, over 21% of older people are affected by mental disorders (e.g., depression or anxiety). Favorably, exercise is known to be an effective alternative for the prevention and treatment of mental health disorders, however, most of this evidence has focused on aerobic training, whereas the effects of resistance training remain unexplored. Thus, the aim of this study is to examine the effects of a 24‐week resistance exercise program on psychological distress in cognitively normal older adults.

Methods

The study included 81 cognitively normal older adults with valid baseline and follow‐up data who were randomly assigned to either a 24‐weeks resistance exercise program (n = 43) or a wait‐list control group (n = 38) as part of the AGUEDA trial (NCT05186090). The exercise program included 3 sessions/week, 60 min each. Psychological distress indicators (i.e., depression‐anxiety symptoms, stress and loneliness) were assessed using a set of valid and reliable self‐reported questionnaires. The effects of the intervention were examined using analysis of covariance (ANCOVA), where post‐exercise outcome values were the dependent variables, group (exercise vs control) the fixed factor, and baseline outcome data the covariates. The intervention effects were presented as z‐scores of changes.

Results

The AGUEDA exercise program had a no effect on anxiety symptoms (z‐score = 0.106), 95% confidence interval (CI): ‐0.514 to 0.126, p = 0.232), stress (z‐score = 0.036), 95% CI: ‐0.313 to 0.449, p = 0.723) and loneliness (z‐score = 0.026), 95% CI: ‐0.315 to 0.432, p = 0.723). There was a borderline, with a small, nonsignificant effect on depressive symptoms (z‐score = ‐0.106), 95% CI: ‐0.752 to 0.051, p = 0.086).

Conclusion

The 24‐weeks exercise intervention had no effect on most of the psychological distress indicators. However, we observed a borderline, small, nonsignificant effect in depressive symptoms. Therefore, future interventions with a larger sample size or longer intervention are needed to confirm these findings.
Periodontitis and future cognitive decline
Authors: McGuinness Bernadette , Passmore Anthony Peter , Holmes Clive , Teeling Jessica , Linden Gerry , Farsi Dominic , McEvoy Claire T , McKay Gareth J , Abadelkareem Rana , Patterson Christopher , McAlinden Michael
Published: December 2023

Background

Periodontitis (gum disease) is a is a chronic inflammatory disorder. Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), Aggregatibacter actinomyecetemcomitans (Aa), and Treponema denticola (Td) are the most common periodontal pathogens. Evidence of a longitudinal association between periodontitis and dementia is currently lacking. We therefore proposed that prior periodontitis in 60‐70 year old men increases the longitudinal risk of cognitive decline.

Method

PRIME‐COG is a nested in PRIME (Prospective Epidemiological Study of Myocardial Infarction), a cohort study of men in Northern Ireland (NI). Between 2001 and 2003, 1400 men underwent a periodontal examination, had inflammatory markers measured in blood, exposure to periodontopathogens identified within dental plaques, and a cognitive assessment. 874 men had a comprehensive cognitive assessment fifteen to twenty years later from which a consensus diagnosis of normal cognition, mild cognitive impairment (MCI) or dementia was made by experienced clinical researchers. Logistic regression models were performed to assess the association between periodontitis and future cognitive endpoints. In addition, serum IgG levels to Pg, Tf, Aa and Td and a panel of pro‐inflammatory cytokines were determined at baseline and follow‐up visits.

Result

We did not identify any significant associations between periodontitis and dementia and/or MCI or cognitive decline in the extended follow up period. No differences in IgG serum titres to pathogens in baseline and follow‐up visits were seen for patients diagnosed with dementia or MCI, whereas levels were significantly decreased in the normal cognition group. Serum levels of IL‐6 at baseline were significantly higher in patients with MCI and dementia compared to those with normal cognition among men aged 76 years plus (p = 0.002); and 81 years plus (p = 0.02) respectively. IL‐8 levels were significantly different in patients with MCI aged 81+ years compared to those with normal cognition at baseline (p = 0.014) and follow‐up (p = 0.012).

Conclusion

Within a cohort of older men residing in the NI, periodontitis was not associated with later onset of dementia or MCI following an extended follow up. Maintenance of high IgG levels over the years might indicate ongoing persistent infection associated with dampened immune response. This could contribute to increased risk of dementia/MCI.