bluuebunny/crossref_metadata_2025 huggingface dataset:
Relative importance of multimodal risk factors to discriminate memory trajectories: Similarities and differences across ethnoracial groups in cognitively normal older adults
Authors: Sapkota Shraddha , Maillard Pauline , Fletcher Evan M , Harvey Danielle J. , Whitmer Rachel A. , Olichney John M. , Jin Lee‐Way , Decarli Charles
Published: June 2023

Background

Inequalities in dementia incidence and heterogeneities observed on memory decline are present across ethnic/racial groups. Research suggests that inequities in risk/protective factors contribute towards these differences. We examine risk factors across multiple domains to identify those that best discriminate differences in memory trajectories across ethnoracial groups.

Method

We used an ethnoracially diverse longitudinal cohort of cognitively normal older adults (n = 299; mean age = 73.47 (6.90) years; 63.9% female) from the University of California, Davis‐Alzheimer’s Disease Research Center. First, we applied latent class growth analysis to objectively classify memory trajectories into distinct latent groups across a maximum of 10 follow‐ups. Second, we used random forest analyses (RFA) to examine relative importance of 22 risk/protective factors from seven domains (demographic, genetic, brain morphometry, plasma and functional biomarkers, psychological and lifestyle factors) to discriminate low/high memory performers as stratified by three ethnoracial groups (African Americans [AA; n = 111]; Hispanics [n = 108], Whites [n = 66]).

Result

First, we observed that four latent classes (low, intermediate, high, very high) best represented memory trajectories (Figure 1). Second, for our RFA analyses, we collapsed low and intermediate groups to a low group (n = 136; 40.4% AA, 25.6% Hispanics, 28.8% Whites), and high and very high to a high performing group (n = 148; 34.6% AA, 50% Hispanics, 15.4% Whites). High memory class was predicted (Figure 2) in AA by lower smoking years, lower Functional Assessment Questionnaire (FAQ), younger age, higher education, lower neurofilament light (NfL), Apolipoprotein E non‐carriers, low neuropsychiatric inventory (NPI) severity, men, and higher hippocampal volume (AUC = 0.73); in Hispanics with men, lower FAQ, lower Geriatric Depression Scale (GDS), smaller third ventricle, larger hippocampal volume, lower NPI severity, smaller lateral ventricle, and lower NfL (AUC = 0.86); and in Whites, with lower FAQ, higher education, higher alcohol use frequency, lower NfL, lower GDS, smaller lateral ventricles, and low white matter hyperintensities (AUC = 0.82).

Conclusion

We observed similarities and differences in predictors to discriminate low versus high memory performers in three ethnoracial groups. Identifying relative importance of risk factors will promote the integration of multimodal risk factors across ethnoracial groups to develop novel and complex risk profiles leading to early detection and identification of asymptomatic or preclinical older adults.
Correlation between inflammatory markers with cognitive function in coronavirus disease‐19 (COVID‐19) patients
Authors: Fitri Fasihah Irfani , Darman Winda Rahmah , Ritarwan Kiking
Published: June 2023

Background

Coronavirus disease‐2019 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and remains an ongoing global pandemic. Although it mainly affects the respiratory system, its manifestation in other organs including nervous system has been increasingly recognized. Previous studies have shown the association between several inflammatory markers with disease severity and mortality in COVID‐19 patients but their association with cognitive function remains unclear. This study aimed to determine the correlation between inflammatory markers with cognitive function in COVID‐19 patients.

Method

This was a cross‐sectional study involving COVID‐19 patients during admission using consecutive sampling method in Adam Malik General Hospital Medan Indonesia. Cognitive function was assessed in several domains using Forward Digit Span (FDS), Backward Digit Span (BDS), and Trail Making Tests A and B (TMT‐A and TMT‐B), to assess attention, working memory and executive function, respectively. We measured neutrophil to lymphocyte ratio (NLR,) C‐reactive protein (CRP), D‐dimer, and ferritin serum levels as inflammatory markers.

Result

This study involved 40 COVID‐19 patients consisting of 13 (32.5%) males and 27 (67.5%) females, the median age value of the patients was 39.5(19‐65) years. We found that higher ferritin level was correlated with worse FDS and BDS scores (r = ‐0.365 p = 0.020 and r = ‐0.408 p = 0.009, respectively)and that d‐dimer level was significantly correlated with worse BDS score (r = ‐0.369 p = 0.019). Higher D‐dimer and ferritin levels were also significantly correlated with longer time of completion of TMT‐B (r = 0.363 p = 0.022 and r = 0.433 p = 0.005, respectively) and higher ferritin level was also correlated with longer time of completion of TMT‐A (r = 0.438 p = 0.005). There were no significant correlation between NLR and CRP level with cognitive function.

Conclusion

Higher inflammatory markers were correlated with attention, working memory and executive function in COVID‐19 patients.
Quantifying neuronal biomarkers in aqueous humor in individuals undergoing routine cataract surgery and correlating with age and cognition
Authors: Robbins Cason B , Wisely C. Ellis , Singh Pali P , Kim Terry , Grewal Dilraj S , Fekrat Sharon
Published: June 2023

Background

Plasma and cerebrospinal fluid (CSF) levels of neuronal biomarkers have been associated with Alzheimer’s disease (AD). The aqueous humor, which can be collected during routine cataract surgery, may have similar concentrations of neuronal biomarkers to CSF.

Method

This proof‐of‐concept study prospectively enrolled adults without a diagnosis of cognitive impairment undergoing cataract surgery at a tertiary academic medical center. Participants underwent Montreal Cognitive Assessment (MoCA blind version 7.1, “abnormal” < 18) at the time of study enrollment. Aqueous samples were collected during cataract surgery through a surgical paracentesis. Samples were analyzed using an ultrasensitive single‐molecule array (SiMoA). Assessed biomarkers included phosphorylated tau (pTau)‐181, amyloid‐beta (Aß)‐42, Aß‐40, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Correlations were assessed using Spearman’s rank correlation (rho).

Result

Sixteen eyes of 16 patients (average MoCA 19.2) underwent aqueous sampling to assess pTau‐181 and 7 eyes of 7 separate patients (average MoCA 20.0) underwent aqueous and plasma sampling to assess Aß‐42, Aß‐40, NfL, and GFAP. Aqueous pTau‐181 increased with increasing age (rho = 0.67, p = 0.0046). No aqueous or plasma biomarkers were significantly correlated with MoCA scores (all p > 0.05). Aqueous and plasma levels of biomarkers were not significantly correlated.

Conclusion

Neuronal biomarkers are measurable in aqueous humor using SiMoA analysis; however, these biomarkers did not significantly correlate with MoCA scores in a cognitively normal population. Further study in individuals with a known diagnosis of Alzheimer’s disease or mild cognitive impairment is indicated.
Early structural brain markers for Alzheimer’s Disease in women: Brain‐behaviour relationships after ovarian removal
Authors: Brown Alana , Gravelsins Laura , Almey Anne , Gervais Nicole J , Duchesne Annie , Rieck Jenny , Reuben Rebekah , Karkaby Laurice , Perovic Mateja , Witt Suzanne Tyson , Classon Elisabeth , Lykke Nina , Theodorsson Elvar , Ernerudh Jan , Lundqvist Elisabeth Åvall , Kjølhede Preben , Morrison India , Novembre Giovanni , Engström Maria , Bernardini Marcus , Foulkes William , Rajah Natasha , Grady Cheryl , Einstein Gillian
Published: June 2023

Background

Women with bilateral salpingo‐oophorectomy (BSO; removal of ovaries and fallopian tubes) prior to age 50 have increased Alzheimer’s disease (AD) risk (Rocca et al., 2007), but the neural mechanisms for this are unclear. Abilities involving manipulation/maintenance aspects of working memory (WM) decline post‐BSO, and this effect may be reduced by estradiol‐based hormone therapy (ET; Gervais et al., 2020). Considering decline in manipulation/maintenance aspects of WM in AD (Germano & Kinsella, 2005), we aimed to understand the relationships between brain structure and WM after BSO.

Method

Women with BSO taking ET (BSO+ET: M±SDage = 44.92±5.11, n = 26) or not taking ET (BSO: M±SDage = 45.62±5.04, n = 26) were compared to age‐matched premenopausal controls (AMC: M±SDage = 43.71±2.92, n = 42) recruited from Toronto, Montreal, and Linköping. T1‐weighted structural magnetic resonance imaging scans were acquired. Voxel‐based morphometry measures of gray matter volume were obtained (CIVET pipeline, Ad‐Dab’bagh et al., 2005). Digit Span Backward (DSB) and Forward (DSF) subtests (Wechsler, 1945) were administered to assess manipulation/maintenance and updating/maintenance aspects of WM, respectively. Multivariate Behaviour Partial Least Squares (McIntosh & Lobaugh, 2004) was used to compare the correlation between performance (DSB and DSF) and volume between groups.

Result

There were no group differences in DSB/DSF total span performance. AMC did not show a significant relationship between volume and WM (Figure1A). For BSO and BSO+ET, gray matter volume in key WM regions, including bilateral supplementary motor area, inferior temporal gyrus, superior and inferior frontal gyri, left precuneus, and right cuneus, was negatively associated with DSB performance (Figure1B warm colours), while hippocampal volume was positively associated with DSB performance (Figure1B cold colours). These relationships were strong for BSO (R = ‐0.78), while BSO+ET (R = ‐0.37; moderate correlation) showed an intermediate phenotype between BSO and AMC (R = 0.14; small correlation).

Conclusion

Manipulation/maintenance aspects of WM and regional volume relationships depended on menopause status and ET. Without ET after BSO, successful WM performance correlated more strongly with hippocampal volume, which is usually the case for high memory load WM tasks (Geva et al., 2016). Even when memory changes are undetected by standard neuropsychological tests, brain‐behaviour relationships may prove a useful tool for assessing early changes in individuals at increased AD risk.
Systems analysis of Alzheimer’s disease pathway dysregulation in human subjects is recapitulated in 3d cellular models to reveal P38 MAPK as a therapeutic target that mitigates tau pathology
Authors: Yeganeh Pourya Naderi , Kwak Sang Su , Jorfi Mehdi , Quinti Luisa , Koler Katjuša , Choi Younjung , Park Joseph , Von Maydell Djuna K , Centinbas Murat , Sadreyev Ruslan I , Tanzi Rudolph E. , Hide Winston , Kim Doo Yeon
Published: June 2023

Background

3D human neural cell culture models of Alzheimer’s disease (AD) are valuable resources for studying AD pathogenesis mechanisms. Although our 3D models capture cellular heterogeneity and key pathogenic cascades in AD, including β‐amyloid (Aβ) accumulation and Aβ‐induced tau pathology, it is not known to what extent 3D models functionally reflect human AD pathogenesis. We address this gap by capturing functionally active AD pathways in human brain through a granular systems approach that accurately recapitulates the activity of disease‐associated pathways from afflicted brain tissues in 3D models.

Methods

We leveraged transcriptomic data to precisely determine the activity dynamics of biological pathways. We assembled transcriptomic data from AD brains and compared them with a battery of 3D models displaying a broad range of disease‐associated characteristics. Our approach discovered pathways showing concordant dysregulation patterns between human brain and disease models. We prioritized the most consistent AD‐pathways for in‐vitro therapeutic screening.

Results

One of our 3D models has transmembrane domain APP mutations, but not PS1 mutations and exhibits an elevated Aβ42/40 ratio. It best recapitulated dysregulated AD‐pathways found in both human prefrontal and temporal cortices. Multiple pathways indicated activation of p38 MAPK signaling, coupled with broad transcriptional inactivation in AD. Cellular and biochemical validations demonstrated elevated phosphorylated‐p38 (p‐tau)/total‐p38 ratios. Treatment with a p38 MAPK inhibitor resulted in significant reduction in the total amount of tau, significant reduction in the amount of p‐tau, and suggestive reduction in p‐tau/tau ratio. Our results strongly support a critical role for p38 MAPK signaling in mediating Ab‐induced tau pathology.

Conclusions

Using human brain transcriptomes, we have introduced a broadly‐applicable systems biology approach to rapidly discover therapeutic targets in 3D models. The approach provides a granular determination of the degree to which cellular models accurately reflect dysregulated molecular pathways in afflicted brains. We have detected, validated, and targeted the activated p38 MAPK pathway in AD. We have diminished tau pathology by inhibiting p38 MAPK signaling in cellular models, suggesting that the p38 MAPK pathway is a potent human‐derived target to combat tau pathology.

PNY and SSK are co‐first‐authors.

RT, WH, and DYK jointly supervised this project.
Application of the modified qualitative scoring of MMSE pentagon test in the differential diagnosis of lewy body dementia and Alzheimer’s disease
Authors: Lu Lu , Zhu Sirui , Meng Xiaosheng , Wang Jing , Li Dan , Li Fangyu , Lu Yuanyuan , Yu Yueyi
Published: June 2023

Background

To explore the value of the modified qualitative scoring of MMSE pentagon test (mQSPT) in the differential diagnosis of Lewy body dementia (DLB) and Alzheimer’s disease (AD).

Method

Study the patients who met the inclusion criteria in the Department of Neurology, Xuanwu Hospital, Capital Medical University from January 2018 to August 2021. The baseline data of gender, age and education, Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA) and Clinical Dementia Assessment Scale (CDR) scores of 61 DLB patients and 71 AD patients were analyzed retrospectively. At the same time, the scores of sub items in the scale that can reflect visualspatial impairment were recorded,: i.e. connection test, cube copy, clock drawing test in MoCA, and pentagon copy test in MMSE. The images in MMSE pentagon copy test of these patients were further scored according to QSPT and mQSPT, and compared between the two groups. Multivariate stepwise logistic regression was used to analyze the differential efficacy of QSPT, mQSPT combined with other clinical psychological evaluation between DLB and AD.

Result

There were significant differences between DLB and AD patients in connection test, cube copy, clock drawing test, pentagon copy test, QSPT, mQSPT and gender, but there were no significant differences in MMSE, MoCA, age and education. The sensitivity of QSPT in differentiating DLB and AD was 71.8%, the specificity was 67.2%, the area under ROC curve was 0.682 (95%CI: 0.584‐0.772), and the cut‐off value was 9.5. The sensitivity of mQSPT in differentiating DLB and AD was 68.9%, the specificity was 84.5%, the area under ROC curve was 0.78 (95%CI: 0.696‐0.862), and the cut‐off value was 8.5. Multivariate stepwise logistic regression showed that while QSPT failed to establish any suitable modeling, mQSPT and cube copy were related to the distinction between the two diseases. Moreover, the efficacy of these two indexes to distinguish AD and DLB: the sensitivity was 70.5%, and the specificity was 84.1% and the area under the ROC curve was 0.817(95%CI: 0.743‐0.891).

Conclusion

The mQSPT can be used for the screening tool in differential diagnosis between AD and DLB patients.
Defining advance care planning from the perspective of people with dementia: Focus groups with the European Working Group of People with dementia
Authors: Monnet Fanny , Pivodic Lara , Dupont Charlèss , Diaz Ana , Gove Dianne , Van den Block Lieve
Published: June 2023

Background

The European Association for Palliative Care (EAPC) defines advance care planning (ACP) as a process enabling individuals with decisional capacity to define goals and preferences for future medical treatment and care, discuss these with family and health‐care providers, and record and review them if appropriate. There are concerns that this and other definitions may not apply to ACP in the context of dementia. ACP needs for people with dementia differ from those of people with other diseases. Furthermore, current definitions are not informed by input from people with dementia, but rely on professional expert recommendations. We gathered the perspectives of the European Working Group of People with Dementia (EWGPWD) regarding the EAPC ACP definition to explore its applicability in the context of dementia.

Methods

We conducted 3 online focus groups with members of the EWGPWD (n = 12) and their supporters (n = 9). We deconstructed ACP in four topics revolving around the what, why, who, and when of ACP to guide discussions. To analyze the data, we used inductive thematic analysis.

Results

Three key issues were highlighted as important to consider in an ACP definition which would be inclusive for people with dementia. First, participants disagreed with the focus on people with decisional capacity, as they saw loss of capacity as a gradual process that depends on context and should be supported throughout the dementia trajectory. Second, although some noted that family dynamics vary, the essential role of families or trust‐based relationships was found to be under‐addressed, as families were generally considered to have personal knowledge of the person with dementia. Third, participants suggested that ACP is too centered on medical care. It should include broader conversations on what matters to people in the future, social care, and future daily life activities.

Conclusion

We identified three points of contention with the EAPC ACP definition corresponding to dementia‐specific issues. The perspectives of the EWGPWD emerging from our focus groups contribute to the understanding of ACP in the context of dementia and highlight the need for a dementia‐inclusive ACP definition focusing on the issues of decisional capacity, family involvement and social aspects of care.
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

Background

Plasma 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.

Method

Plasma 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.

Result

In 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.

Conclusion

Plasma 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

Background

The 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.

Method

Here, 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).

Results

The 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.

Conclusion

Legacy 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

Background

Psychosocial 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.

Method

Using 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)).

Result

Repeated 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.

Conclusion

Psychosocial 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

Background

Frontotemporal 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.

Method

Longitudinal 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.

Result

Relatively 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.

Conclusion

This 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

Background

G‐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.

Result

Both [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).

Conclusion

Radiochemistry 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

Background

Type 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.

Method

This 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.

Result

Compared 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.

Conclusion

Our 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

Background

Structural 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.

Method

All 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.

Result

The average classification accuracy, sensitivity, and specificity were achieved at 65.0%, 86.7%, and 23.2% respectively.

Conclusion

Structural 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

Background

Akt 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.

Methods

We 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.

Results

We 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.

Conclusions

Our 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

Background

Arterial 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.

Method

Arterial 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.

Result

Among 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.

Conclusions

Arterial stiffness is associated with microstructural and macrostructural differences and poorer global and executive cognitive function.
The impact of increasing levels of blood C‐reactive protein on the loci for inflammatory, SPI1 and CD33, for Alzheimer’s disease
Authors: Huang Jinghan , Tao Qiushan , Ang Ting Fang Alvin , Farrell John , Zhu Congcong , Wang Yixuan , Stein Thor D. , Lunetta Kathryn L. , Massaro Joseph , Mez Jesse B. , Au Rhoda , Farrer Lindsay A. , Qiu Wei Qiao , Zhang Xiaoling
Published: June 2023

Background

Previously, we found that elevated blood C‐reactive protein (CRP) increased the impact of the apolipoprotein ε4 allele (APOE ε4) on the risk of Alzheimer’s disease (AD).1 In this study, we hypothesized that interactions between CRP and other AD‐associated genes also increase AD risk.

Method

SNPs in 10 AD risk loci, which also encode proteins related to inflammation, were used to test interaction with CRP on AD risk using additive model or dominant model with Cox proportional hazards regression and survival analysis.

Result

There were 279,176 UKBB white participants with average age (mean±SD) 60.1 ± 5.5 years including 53.9% females and 803 (0.3%) incident AD cases among 8.3 ± 0.9 years follow‐up on average. We found that for higher concentrations of serum CRP, the AD risk increased for SNP genotypes in 3 AD associated genes (SPI1, CD33 and CLU). Using Cox proportional hazards model in stratified genotype analysis, the hazard ratios (HR) for the association between higher CRP level (≥ 10 vs < 10 mg/L) and the risk of incident AD were 1.94 (95% CI: 1.33‐2.84, p<0.001) among SPI1 rs1057233‐AA genotype, 1.75 (95% CI: 1.20‐2.55, p = 0.004) for CD33 rs3865444‐CC genotype, and 1.76 (95% CI: 1.25‐2.48, p = 0.001) for CLU rs9331896‐CC+CT genotype, respectively. All models adjusted for age at baseline, sex, years of education, APOE ε4 and population principal components. In contrast, these associations were not observed in the other genotypes of these genes. Similar results for SPI1 and CD33 genotypes impacted by elevated CRP levels were observed for MCI to AD conversion and CSF AD biomarkers including t‐Tau and p‐Tau in the ADNI cohort (p<0.01).

Conclusion

Elevated blood CRP released in peripheral inflammation may be an important mediator in the association of genetic variants in SPI1, CD33 and CLU in addition to APOE ε4 for AD risk. Monitoring of CRP levels may be useful for more precise intervention and prevention of AD for these genotype carriers.

1. Tao Q, Ang TFA, DeCarli C, et al. Association of Chronic Low‐grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers. JAMA Netw Open. Oct 5 2018;1(6):e183597. https://doi.org/10.1001/jamanetworkopen.2018.3597
Haploinsufficiency of progranulin causes cell type specific impairments in PINK1/Parkin mitophagy
Authors: Casey Jackie M. , Melandri Daniela , Arber Charles , Soutar Marc , Holler Christopher J. , Kukar Thomas , Isaacs Adrian M , Rohrer Jonathan D. , Pocock Jennifer M , Plun‐Favreau Helene , Wray Selina
Published: June 2023

Background

GRN mutations that result in progranulin haploinsufficiency cause frontotemporal dementia (FTD). Mitophagy, the selective autophagy of damaged mitochondria, is impaired in several neurodegenerative diseases. A number of genes linked to FTD (e.g. OPTN, SQSTM, VCP and TBK1) are also known to play a role in mitophagy. Xenophagy, the selective autophagy of non‐host pathogens, relies on some of the same proteins as mitophagy (Parkin and TBK1) and is reduced in GRN knockout mice. Progranulin has also been found to play a role in mitophagy in mouse kidney cells. We therefore hypothesised that loss of progranulin could lead to defective mitophagy in neurons, astrocytes and microglia.

Methods

We investigated PINK1/Parkin mitophagy in astrocytic‐like H4 cells and neuron‐like Parkin overexpressing SHSY5Y cells (PoE‐5Ys) +/‐ siRNA against GRN. We also examined induced pluripotent stem cells (iPSCs) from four controls, three patients with FTD‐associated GRN mutations (R493X and C31fs) and a CRISPR series from the human iPSC Neurodegenerative Disease Initiative1,2,3 (iNDI) with an isogenic control, heterozygous and homozygous R493X mutation lines. The iPSCs were differentiated to cortical neurons, astrocytes and microglia. PINK1/Parkin mitophagy was induced using Antimycin A (respiratory complex III inhibitor) and oligomycin (ATP synthase inhibitor). PINK1 accumulation, levels of S65 phosphorylated ubiquitin (pUb), other mitophagy markers as well as proteins hypothesised to play a role in the mechanism were examined using western blotting and immunofluorescence (ICC).

Results

Lower levels of pUb were detected in PoE‐5Ys treated with oligomycin/antimycin following GRN knockdown. There was a significant reduction in mitophagy in GRN siRNA treated H4 cells, detected by ICC and western blotting of mitophagy markers. Initial results from iPSC neurons found no significant difference in mitophagy between control and patient lines. Work is ongoing in a larger set of iPSC neurons, astrocytes and microglia. Preliminary results suggest that reducing progranulin affects mitophagy in astrocytes but has a limited effect on mitophagy in neurons.

Conclusions

The results suggest that progranulin has a cell specific role in mitophagy with progranulin regulating stability and/or activity of PINK1. Current work aims to understand the mechanisms of this process and to dissect cell‐type specific contributions of progranulin to mitophagy.