bluuebunny/crossref_metadata_2025 huggingface dataset:
2.Cerebrovascular neuropathology in the brains of people with Down syndrome
Authors: Aguilar Lisi Flores , Head Elizabeth
Published: December 2023

Background

People with Down syndrome (DS) are at genetic risk of developing early‐onset Alzheimer’s disease (AD). By age 40 years, virtually all people with DS develop beta amyloid plaques and tau neurofibrillary tangles, typically followed by the development of AD dementia over a decade later. Despite having a low frequency of vascular risk factors (i.e., hypertension, atherosclerosis), people with DS show an age‐related progression of cerebral amyloid angiopathy (CAA), white matter hyperintensities, microbleeds, micro infarcts, and enlarged perivascular spaces by neuroimaging. Interestingly, the incidence of CAA at autopsy is significantly higher in people with DS than patients with late onset AD. Our main objective is to investigate the cerebrovascular pathology in DS autopsy cases.

Method

Free floating 30 µm thick sections from the occipital cortex of DS cases with or without AD pathology (DSAD and DS, respectively, n = 5/group) were compared to age matched cognitively normal controls (n = 5). Sections were immunostained for collagen IV (basement membranes) and for fibrinogen (protein extravasation).

Result

Preliminary results show that compared to controls, DSAD brains have impaired vascular integrity, observed as reduced collagen IV basement membrane labeling and evidence of protein extravasation which may reflect microbleeds observed using in vivo neuroimaging.

Conclusion

Our preliminary data suggest a disruption of blood vessel basement membranes observed as losses in collagen IV immunostaining in DSAD brains. Moreover, fibrinogen extravasation was consistently observed in DSAD brains. We are currently characterizing the age of onset of collagen IV disruption/losses and fibrinogen leakage into the brain parenchyma in the context of an AT(N) framework to understand when in AD progression, cerebrovascular pathology evolves in DS.
3. Neuropathological differences between Down syndrome and familial Alzheimer’s disease with APP duplication: role of endothelial cells in cerebral amyloid angiopathy.
Authors: Potier Marie‐Claude
Published: December 2023

Background

While amyloid plaques are common in all AD cases, CAA is mainly found in familial AD with duplications of the APP gene (DUP‐APP), Down Syndrome (DS), and specific APP mutations. Mechanisms leading to these differences are not yet understood. We investigated the diversity of neuropathological phenotypes and the composition of brain Aß peptides in sporadic AD (sAD), DUP‐APP, APP mutations, DS with or without dementia (D), and control cases. In addition, we analysed endothelial cells derived from iPSC lines (iPSC‐d‐ECs) of patients to model the vessel wall forming the blood‐brain barrier.

Method

We analyzed Aβ and Tau pathologies in post‐mortem human brain tissues by immunohistochemistry on paraffin‐embedded sections (12 sAD, 7 DUP‐APP, 3 DS, 10 DS‐D and 9 APP mutations cases). Using immunoprecipitation and mass spectrometry, we characterized Aß species in brain homogentes from the same cases. We analysed the morphology of iPSCs‐d‐ECs, measured their levels of Aβ secretion and junctional proteins and analysed their transcriptomes.

Result

Aβ deposits in the parenchyma were found in sAD, DS‐D and APP mutations, and less abundant in DUP‐APP. Conversely, Aβ deposits in the blood vessels (arteries and arterioles) were prominent in DUP‐APP, less abundant in DS‐D and even less frequent in sAD and APP mutations. Only DUP‐APP cases showed Aβ deposits in the capillaries. Despite striking differences in Aβ pathologies, all cases with dementia had high Tau pathology. Aß peptides signatures were different in cases with CAA, with higher levels of shorter Aß peptides and truncated species at position 2 at the N‐terminus. iPSC‐d‐ECs secreted substantial amounts of Aβ peptides. We identified changes in the morphology and tight junctions of iPSC‐d‐ECs with DUP‐APP as well as specific gene expression dysregulations, suggesting intrinsic remodelling of ECs of the blood‐brain barrier in DUP‐APP.

Conclusion

Our study reveals new pathophysiological mechanisms involved in specific Aβ production and deposition in the blood vessel wall of patients carrying DUP‐APP involving EC. Differences between DUP‐APP and DS suggest the presence in the DS population of protective factors against CAA.
Hippocampal administration of astrocyte‐derived extracellular vesicles (AEVs) exacerbates motor deficits and impairs spatial memory in a mouse model of Alzheimer’s Disease
Authors: Winston Charisse N. , Rissman Robert A
Published: December 2023

Background

Understanding the therapeutic and/or pathogenic potential of extracellular vesicles (EVs) and their cargo has emerged as an important topic in relation to development of Alzheimer’s disease (AD) and other age‐related dementias (ADRD). Here, we tested the impact of treatment of astrocyte‐derived plasma EVs on cellular and functional recovery was explored in aged, AD (PSAPP) mice.

Method

Plasma EVs derived from normal controls, mild cognitively impaired (MCI), and AD subjects (n = 7 = /group) were extracted, precipitated using a polymer‐based isolation method (ExoQuick), and enriched against an astrocyte (GLAST) source using magnetic immunocapture and fluorescence‐activated cell sorting. Pooled AEV preparations were injected unilaterally into the right hippocampus of 7m old, female, PSAPP mice. AD‐related neuropathological changes and functional deficits in spatial learning and memory (Morris Water Maze), gait stability (rotarod) and anxiety (SLMA) were assessed at 7 months post injection (mpi).

Result

We observed MCI and AD AEV injected mice took a longer time and traveled a shorter distance to reach the cued and hidden platform as compared to mice injected with AEVs from normal controls. After the platform was removed, we observed MCI and AD AEV injected mice made significantly fewer entries into the correct quadrant zone and fewer entries into the correct target zone where the platform was originally located. Motor function was significantly impaired in MCI and AD AEV injected mice as compared to control AEV injected mice. Behavioral impairments correlated with increased gliosis, as measured by Iba1 and GFAP, and increased plaque burden, as measured by 6E10 antibody, in the brains of MCI and AD AEV injected mice. Similar levels of phosphorylated tau immunoreactivity were observed in all three mice groups.

Conclusion

AEVs derived from cognitively impaired subjects transfer toxic proteins to hippocampal cells and exacerbate functional impairments and AD neuropathology in vivo. Cellular and functional recovery was observed in mice injected with EVs from control subjects.
MR imaging of Brain blood flow in young and older adults with Down syndrome.
Authors: Tamayo‐Elizalde Miren , Saini Fedal , Idris Mina , Dell'Acqua Flavio , Zelaya Fernando , Strydom Andre
Published: December 2023

Background

The trisomy of chromosome 21 that causes Down syndrome (DS) predisposes to Alzheimer’s disease (AD) with a lifetime risk of >90% [1]. The overexpression of the amyloid precursor protein gene leads to amyloid‐β accumulation in the brain and, by age 40, most individuals with DS show AD neuropathology [2]. Amyloid deposits in the brain affect the parenchyma and the blood vessels.

While cerebral blood flow (CBF) is substantially reduced in sporadic AD [3], particularly in the temporal and parietal lobes involved in memory and language, the cerebrovascular neuropathology ubiquitous in DS from early adulthood is not well characterised, and the link between CBF and the development of dementia symptoms in adults with DS is still unclear.

Here, we compare localised cerebral perfusion in young and older adults with DS, and hypothesise hypoperfusion in older adults in areas that are commonly affected in AD.

Method

Arterial Spin Labeling (ASL) data was acquired from a total of 33 individuals with DS with ages between 17 and 58, of which 16 were classified as young adults (YA, < = 35 years), and 17 as older adults (OA, >36 years). CBF maps were generated for each subject from ASL images using the ASAP toolbox [4].

A two‐sample t‐test statistical group analysis was then conducted between CBFs from YA and OA on SPM12 [5] with age and sex as covariates.

Result

Group analyses showed significant hypoperfusion in OA relative to YA in areas that included the precuneus, prefrontal and orbitofrontal areas, and regions involved in sensory and motor integration. Some of these are known to be affected in AD and are regions where amyloid aggregations start to occur.

The association of these hypoperfusion changes with cognitive scores will also be presented.

Conclusion

There are significant hypoperfusion changes associated with age in individuals with DS in areas known to be affected in AD.

[1] McCarron M. et al, J Intellect Disabil Res., 2017

[2] Lott and Head, Nat. Rev. Neurol., 2019

[3] Roher, A. E. et al, Vasc Health Risk Manag, 2012

[4] Abad, V. M., et al, Magn. Reson. Imaging, 2016

[5] https://www.fil.ion.ucl.ac.uk/spm/ [Accessed on 10/12/2022]
Modelling of the development and response to amyloid‐β accumulation in the context of trisomy21 in the rodent brain
Authors: Farrell Clíona , Mumford Paige , Beament Millie , Lau Gloria , Wu Yixing , Pellen Marion , Baniowska Monika Rataj , Tosh Justin , Noy Sue , Cleverley Karen , HERAULT Yann , Tybulewicz Victor , Fisher Elizabeth , Wiseman Frances K
Published: December 2023

Background

Individuals who have Down syndrome (DS), a genetic condition caused by having three copies of chromosome 21, frequently develop early‐onset Alzheimer’s disease (AD). This is caused by the additional copy of the APP gene, located on chromosome 21, which leads to a raised abundance of amyloid‐β. However, significant evidence demonstrates that the additional copy of other genes on the chromosome modifies the accumulation and response to amyloid‐β. Here we present a series of rodent preclinical models of AD‐DS, which we use to investigate this biology and can be used to test potential therapeutic approaches.

Methods

We previously crossed mouse models of DS with the AppNL‐F model of amyloid‐β accumulation; demonstrating that three copies of a region of chromosome 21 containing 38 genes is sufficient to reduce the accumulation of amyloid‐β. Here we present new data from a cross of the Dp1Tyb DS mouse model with an App gene knock‐out (to normalise the number of copies of this gene) and novel DS‐AD rodent models in which the endogenous App gene has been partially humanized (Dup(Rno11)‐APP‐H3 and Ts68Yah) compared with DS model controls (Dup(Rno11) and Ts66Yah). Brain material from these models at a range of ages was analyzed by western blot, biochemical fractionation and MSD assay, and immunohistology to study APP processing and amyloid‐β accumulation. We used MSD assay and immunofluorescence to study the response to accumulating amyloid‐β with a focus on the response of microglia, neuroinflammation and break‐down of the blood‐brain barrier.

Results

Our data indicate that three copies of App contribute to altered microglia biology in the Dp1Tyb mouse model of DS and that partial humanization of the App gene in DS rodent models leads to alterations in the processing of APP, and results in raised levels of human amyloid‐β in the brain.

Conclusion

These new model systems of DS‐AD amyloid‐β biology can be used to better understand the early development of AD in people who have DS and to test the safety and efficacy of new therapies for this important group of individuals who are at extremely high risk of developing early onset dementia.
Diffusion tensor image analysis along the perivascular space inversely correlates with age in healthy subjects
Authors: Ozsahin Ilker , Zhou Liangdong , Wang Xiuyuan Hugh , Garetti Jacob , Xi Ke , Tanzi Emily , Kuceyeski Amy , Shah Sudhin , Li Yi , Butler Tracy A
Published: December 2023

Background

The glymphatic system is a brain waste fluid clearance system. Glymphatic dysfunction of glymphatic system has been seen in normal aging in many neurological diseases. Diffusion tensor image analysis along the perivascular space (DTI‐ALPS) is a novel MRI method to assess the glymphatic function. In this study, we aim to evaluate the changes in glymphatic system by aging with DTI‐ALPS method.

Method

We investigated DTI‐ALPS indices of 49 healthy subjects underwent MRI scans. Anatomical T1w MPRAGE and multi‐shell diffusion‐weighted MRI were acquired on a 3T Siemens Prisma scanner. Diffusion MRI (dMRI) images were corrected for distortions induced by susceptibility and eddy current. To evaluate the glymphatic system activity, an index called ALPS index was calculated. Linear regression analysis was used to evaluate the correlation of age and ALPS.

Result

Results showed that DTI‐ALPS index inversely correlates with age: R = ‐0.42, p<0.05, meaning glymphatic system activity inversely correlates with aging in healthy subjects.

Conclusion

Understanding the factors affecting glymphatic function might help better understanding the underlying mechanism of neurological diseases and healthy aging.
Speech for Intelligent cognition change tracking and DEtection of AD (SIDE‐AD) Research Program: SIDE‐AD
Authors: Haider Fasih , Saunders Stina , Muniz‐Terrera Graciela , Ritchie Craig W , Luz Saturnino
Published: December 2023

Background

There is emerging evidence that speech could be a potential indicator and manifestation of early Alzheimer’s disease (AD) pathology. Symptomatic AD may change an individual’s language, especially certain elements in speech such as elaboration and attribution. Therefore, the University of Edinburgh and Sony Group Corporation are collaborating within the Sony Research Award Program to create the SIDE‐AD study which aims to develop digital speech‐based biomarkers technology for AD. The study is designed to assess disease status in the pre‐dementia stages in a real‐world at‐risk population in Brain Health Services.

Method

SIDE‐AD is an observational longitudinal study developing speech biomarkers for use in neurodegenerative disease. Participants are recruited from Brain Health Services in Scotland with data collection starting in spring 2023. In the context of the SIDE‐AD study, we have developed a secured online data collection infrastructure for collecting voice data by prompting individuals to record a voice sample talking about their brain health. Individuals are asked to rate their mood, anxiety and apathy. The baseline speech biomarkers will be compared to the follow‐up visit’s speech recordings as well as to other variables from routinely collected health care data. The SIDE‐AD study will employ signal processing and machine learning technologies to automate the assessment of the respondents’ speech.

Result

The objective of the SIDE‐AD study is to recruit participants (n = 150) across the AD spectrum. The developed infrastructure will be used to collect data of participants with an objective of analysing baseline speech markers in relation to self‐reported mood, anxiety and apathy as well as clinical outcomes from patients’ health care records.

Conclusion

The SIDE‐AD study is carrying out research and development of a speech‐based application recording data on individuals’ self‐perceived brain health. A secured online data collection infrastructure is developed to collect speech data with an objective to analyse speech data in combination with routinely available clinical data in Brain Health Clinics, enabling real world validation of speech‐based digital biomarkers for the early detection of AD. We plan to use automatic speech recognition and acoustic patterns for the automatic assessment of brain health status relevant to emergent AD‐specific speech biomarkers.
APP/AICD‐dependent expression of Glypican 4 mediates accumulation of tau oligomers in astrocytes and their synaptotoxic action
Authors: Piacentini Roberto , Puliatti Gulia , Puma Domenica Donatella Li , Aceto Giuseppe , Acquarone Erica , D'Adamio Luciano , Ripoli Cristian , Arancio Ottavio , Grassi Claudio
Published: December 2023

Background

Several studies including ours reported the detrimental effects of extracellular tau oligomers (ex‐oTau) on glutamatergic synaptic transmission and plasticity. Astrocytes greatly internalize ex‐oTau thus contributing to their clearance. However, glial cell engulfment of oTau leads to alteration of neuro/gliotransmitter handling that negatively affects synaptic function. We previously reported that amyloid precursor protein (APP) is required for oTau internalization in astrocytes but the molecular mechanisms underlying this phenomenon has not been clearly identified yet. Here we investigated the role of glypican 4 (GPC4), a member of the large family of heparan sulfate proteoglycans that are membrane glycoproteins highly expressed in astrocytes playing a critical role in protein trafficking through the plasma membrane.

Method

The role of GPC4 in ex‐oTau accumulation in astrocytes and the resulting synaptotoxic action were studied in in vitro and ex‐vivo models obtained from wild‐type C57/bl6 and transgenic mice in which either APP was knocked‐out or it contained the non‐phosphorylatable amino acid alanine replacing threonine 688 (APPTA mice). In these experimental models we performed immunofluorescence analyses, Western blot and real‐time PCR experiments, confocal Ca2+ imaging, high‐pressure liquid chromatography, FM1‐43 imaging, electrophysiological recordings and Chromatin immunoprecipitation assays.

Result

Treatment of cultured astrocytes with a specific anti‐GPC4 antibody significantly reduced oTau internalization in astrocytes and prevented oTau‐induced alterations of intracellular Ca2+ signaling and gliotransmitter release. As such, anti‐GPC4 treatment spared neurons from the astrocyte‐mediated synaptotoxic action of ex‐oTau. Specifically, after counteracting the interaction between ex‐oTau and GPC4 no significant decreases in synaptic vesicular release and synaptic protein expression were observed in neurons co‐cultured with astrocytes following exposure to ex‐oTau. The latter also failed to inhibit hippocampal LTP at CA3‐CA1 synapses. Of note, we found that the expression of GPC4 depended on APP and, in particular, on its C‐terminal domain, AICD, generated by γ‐secretase‐dependent cleavage of APP, that can bind Gpc4 promoter. Accordingly, GPC4 expression was significantly reduced in both APP‐KO ad APPTA mice, and ex‐oTau did not exert any significant detrimental action on synaptic function in APP‐KO mice.

Conclusion

Collectively, our data indicate that GPC4 expression is APP/AICD‐dependent, it mediates oTau accumulation in astrocytes and the resulting synaptotoxic effects.
Distinct pattern of tau‐induced effects in the compartments of the tripartite synapse
Authors: Arancio Ottavio , Argyrousi Elentina K , Kim Young B , Zhang Hong , Nicholls Russell E
Published: December 2023

Background

Tau‐induced synaptic dysfunction is thought to play a key role in the memory decline of Alzheimer’s disease (AD). Synapses are complex multicomponent structures that – in the case of glutamatergic central synapses – are made up of presynaptic, postsynaptic and astrocytic cells that interact with one another to regulate synaptic activity and plasticity. However, since the majority of studies aimed at understanding tau‐induced synaptic impairments were performed on preparations with broadly distributed mutant tau expression, the contribution of tau’s pathological actions in particular synaptic compartments to these impairments is largely unknown.

Method

In order to restrict expression of pathological tau to presynaptic, postsynaptic and astrocytic cells at Schaffer collateral synapses in the mouse hippocampus, we developed a method using a novel tau‐expressing viral vector together with Cre recombinase‐expressing transgenic mice. Electrophysiological analysis of different forms of synaptic plasticity was performed in mouse hippocampal slices 13‐14 days after intra‐hippocampal injection.

Result

Expression of mutant tau in presynaptic cells of the hippocampus lead to impairment of long‐term potentiation (LTP) and long‐term depression (LTD), as well as paired‐pulse facilitation (PPF) and synaptic fatigue (SF), but not post‐tetanic potentiation (PTP). Postsynaptic expression leads to defects in LTP, PPF and PTP, while LTD and SF were unaffected. Finally, expression of pathological tau in hippocampal astrocytes had a negative impact on LTP, PPF, PTP, SF, but not LTD.

Conclusion

These results suggest that tau elevation in the different cells of the tripartite synapse could lead to a compartment‐specific electrophysiological footprint. Besides extending our knowledge regarding the action of pathological tau in AD, these results are important for the development of combinatorial therapeutic approaches effective for the various synaptic impairments.
Using Natural Language Processing to identify psychiatric symptoms related to Alzheimer’s disease: a novel tool to enhance molecular brain research in Alzheimer’s disease
Authors: Vogelgsang Jonathan , Jiang Weiqian , Dan Shu , Vempati Sangeetha , Chatigny Michael , Abston Joshua , Durning Peter , McCoy Thomas , Klengel Torsten , Berretta Sabina
Published: December 2023

Background

Neuropsychiatric symptoms (NPS), such as anxiety, depression, or agitation, are common across different stages of Alzheimer’s disease (AD). However, their molecular course is still poorly understood. While post‐mortem brain research provides a unique source to study brain‐specific molecular changes, clinical characterization of post‐mortem brain donors is challenging and primarily subject to case‐control designs. Here, we present a novel approach to post‐mortem brain donor characterization using natural language processing (NLP).

Method

We analyzed electronic health records (HER) of 92 brain donors (46 males, 46 females, mean age 81.9 years, B&B 0 ‐ VI) using NLP‐based NIMH Research Domain Criteria (RDoC) quantification. Individual RDoC scores were regressed to their neuropathological findings or RNAseq data from two independent brain regions, BA32 and insula.

Result

Neuritic plaques (NP) in all four cortices show a high association with RDoC “cognition”, controlled for age and sex (frontal: ß = 0.38, p < 0.001; parietal: ß = 0.35, p < 0.001; temporal: ß = 0.37, p < 0.001; occipital: ß = 0.37, p < 0.001). These findings align with prior clinicopathological correlation studies where cognitive examinations were performed within one year before death (Nelson et al., J Neuropathol Exp Neurol, 2012).

At pFDR<0.05, we identified 492 differentially expressed genes (DEGs) in the insula and 333 DEGs in the BA32. We have further built a model regressing individual RDoC levels against their DEGs in the two brain regions. In each domain, we observed a cluster of genes that is up‐ or downregulated in relation to their RDoC score (higher/lower domain burden). In addition, we saw that the majority of DEGs are RDoC‐specific. 223 DEGs were uniquely related to one domain (170 DEGs in the insula and 53 DEGs in BA32), while a total of 211 DEGs were associated with at least two domains (151 DEGs in the insula and 60 DEGs in BA32).

Conclusion

NLP‐based analysis of RDoC can be applied to post‐mortem case collections to phenotype brain donors and show promising associations with neuropathology or RNAseq data that can be used to discover novel molecular pathways related to psychiatric symptoms.
Scoring Accuracy of the Self‐Administered Gerocognitive Examination by Primary Care Providers
Authors: Scharre Douglas W. , Vrettos Nicole E , Nagaraja Haikady N
Published: December 2023

Background

Primary Care Providers (PCPs) are critical for case finding of Mild Cognitive Impairment to provide management, referrals, and treatments. Conducting cognitive assessments are time consuming and difficult to incorporate into time‐limited visits. The Self‐Administered Gerocognitive Examination (SAGE) is a reliable and valid, pen and paper, cognitive assessment tool easily incorporated into a PCP visit without time required for staff to administer. Accurate scoring by PCP or staff is critical to interpreting the degree of impairments and any changes over time.

Methods

Patients over 64 years‐old without a diagnosed cognitive disorder, presented for a non‐acute care visit with their PCP and were given a SAGE test during their appointment. The SAGE was administered as part of the provider’s standardized method for screening for cognitive impairment. Detailed scoring instructions were provided to the PCP office before subject enrollment. Differences in SAGE scoring between the PCP office and the Ohio State University Memory Disorders Research Center (MDRC) were evaluated. Paired t test and 95% confidence interval were used to compare the mean SAGE scores.

Results

Of the 110 potential recruits, 93 SAGE tests were graded by the PCP office and by MDRC. Scoring discrepancies, the MDRC scored SAGE minus PCP office scored SAGE, ranged from ‐7 points to +3 points with a total of 80% of the SAGE tests resulting in a scoring error by the PCP office; 74% of the total score discrepancies were within ± 2 points. The mean difference was ‐1.49 with a 95% CI (‐1.82, ‐1.17) and p<0.0001 with PCPs scores tending about 1.5 points higher. The largest discrepancies between the scores occurred with the problem‐solving question (40%) and the 3‐D figure question (29%).

Conclusions

The PCP office provided an incorrect score (typically higher) 80% of the time which downplays cognitive deficits. When scoring mistakes are made, accuracy is diminished, impacting the interpretation of the test results and perceived changes over time. PCP offices need to emphasize accurate scoring or consider utilizing the digital format of SAGE, called eSAGE or BrainTest® (available at https://braintest.com). It can send HIPPA compliant automatically scored results to the PCP office.
Changes in cognitive impairment after multidimentional rehabilitation in Neuro COVID severe respiratory failure patients
Authors: Carabelli Valeria P , Previgliano Martin J , Foster Carolina , Previgliano Ignacio J
Published: December 2023

Background

A Post Intensive Care Syndrome Unit (PICSU) was developed during COVID 19 pandemic. The aim of this study was to evaluate Cognitive Impairment (CI) evolution after PICSU treatment in Neuro COVID patients.

Methods

Prospective observational study. Population: Neuro COVID patients treated in a PICSU. CI was achieved by means of the Spanish version of the MoCA at ICU discharge and one month after, muscle function was evaluated by means of Medical Research Council test for Intensive Care Acquired Weakness (ICUAW). Statistical analysis was performed by ANOVA and Chi squared test. Age, sex, comorbidities, mechanical ventilation days and length of stay at the PICSU wre also measured.

Patients were submitted to an intensive rehabilitation program that included physical, swallowing, speech therapy, occupational therapy ones, as well as nutritional and psychological support.

Results

27 patients were admitted to PICSU, 5 were female, average age was 57 yo. 30% of them presented normal cognition. Regarding CI patients mean initial MoCA value was 18 and improved to 23 (p < 0.05), MRC values were 42 y 52 respectively (p < 0.05). According MoCA values using a cutoff point of 26 to determinate normal cognition, 16 to 25 for MCI and 15 for Mild Dementia, 26% had MCI and 74% at ICU discharge that evolved to normal (26%), MCI (58%) and MD (16%) (p < 0.05). There was a close relationship between MoCA and MCR enhancement, CI and ICUAW improved simultaneously (p < 0.05).

Conclusion

PICSU rehabilitation program was useful for cognition and motor function improvement. The close relationship between cognition and motor function could be explained by the myokines and neurotrophic factors release toward muscle activity. This could be an opportunity for future research.
Identifying preclinical Alzheimer’s disease in the community with brief automated hand movement analysis: validation against plasma ptau181 and asymptomatic episodic memory decline
Authors: Alty Jane E , Bai Quan , Wang Xinyi , Li Renjie , Lawler Katherine , George Rebecca J St , Bindoff Aidan D , Roccati Eddy , Bartlett Larissa , Huang Guan , Rudd Kaylee , Collins Jessica M , Garg Saurabh , Hinder Mark , King Anna E , Vickers James C
Published: December 2023

Background

Dementia prevention and drug development is hindered by the lack of low‐cost population‐level tests to help identify preclinical Alzheimer’s disease (AD) in the community. Recent evidence suggests that precise analysis of hand movements may detect motor changes indicative of preclinical AD. The objective was to evaluate how TAS Test, a new online automated hand movement test, predicts preclinical AD biomarkers (plasma ptau181 and subtle episodic memory decline) in a cognitively asymptomatic cohort of older adults.

Method

Participants completed TAS Test online at home using their own computer without researcher assistance: a series of 10‐30 second index finger‐key and index finger‐thumb tapping tests recorded with a keyboard and/or webcam. Movement features including frequency, rhythm, pauses and accuracy were extracted. Participants also completed online tests of episodic memory, CANTAB Paired Associate Learning (CANTAB). A subset provided blood samples for ptau181 analysis. Accuracy of linear regression models comprising hand motor features to predict PAL scores and ptau181 levels, adjusted for confounding, was compared to null models (with only confounders: age, gender, education level, anxiety and depression) using R2
adj and AIC. ΔAIC > 2 denotes statistical difference.

Result

1,228 adults (mean (SD) age, 65.8 (7.4) years; 73.0% female) completed TAS Test and CANTAB; 459 underwent ptau181 analysis. All keyboard tests improved prediction of asymptomatic episodic memory decline; the 3 step‐ (ΔAIC = 11.2; R2
adj = 8.1%) and alternate‐ key (ΔAIC = 3.3; R2
adj = 7.5%) tests ranked highest and were the only keyboard tests to improve prediction of ptau181 (3 step ΔAIC = 7.0; R2
adj = 17.8%; alternate key ΔAIC = 3.4; R2
adj = 17.4%). All finger‐thumb motor measures improved predictions of CANTAB scores and ptau181 levels; the highest performing tests were dominant hand tapping (CANTAB ΔAIC = 2.9; R2
adj = 8.2%; ptau181 ΔAIC = 2.4; R2
adj = 12.9%) and both hands dual‐task tapping (CANTAB ΔAIC = 3.0; R2
adj = 6.8%; ptau181 ΔAIC = 8.7; R2
adj = 11.9%).

Conclusion

TAS Test provides an accessible brief home‐based test for identifying preclinical AD risk. This novel approach holds potential as a pre‐screening/enrichment tool for identifying at risk cohorts for further investigation.
Identifying genes associated with Alzheimer’s disease using gene‐based polygenic risk score
Authors: Lai Dongbing , Zhang Michael , Li Rudong , Zhang Chi , Zhang Pengyue , Liu Yunlong , Gao Sujuan , Foroud Tatiana M.
Published: December 2023

Background

Recent large‐scale genome‐wide association studies (GWAS) have identified >100 Alzheimer’s disease (AD) associated genes but together they only explain a small portion of AD heritability1‐11. Dramatically increasing the sample size can detect genes with small effects but it is not feasible in the near future. If polygenic risk score (PRS) calculated using SNPs located within genes (gene‐based PRS) has higher predictability, then these genes are likely AD‐associated. Additionally, many drugs target AD‐associated genes and they should be prioritized for future investigations.

Method

We used SNPs having the same directions of effects (concordant SNPs) in different large‐scale European ancestry AD GWAS cohorts (Kunkle et al, 20194,9, the UK Biobank8,9, FinnGen consortium1,12) to calculate gene‐based PRS. Retaining concordant SNPs excludes cohort‐specific findings and reduces false positives, thereby improving PRS predictability. We used megaPRS13 to measure the PRS predictability, which can use GWAS summary statistics as the target dataset13. Leave‐one‐cohort‐out (LOCO) strategy was used and for each LOCO, two GWAS cohorts were used as the discovery dataset and the third cohort was used as the target dataset. Genes identified by all three LOCOs were considered as AD‐associated. Given the large effect of APOE on AD prediction, LOCO was also performed excluding APOE. We then searched the Drug Gene Interaction Database14 for drugs targeting AD‐associated genes. To prioritize identified drugs, we use lmQCM15 and the STRING database16 to identify AD‐associated genes in the same co‐expression module or in the same protein‐protein interaction (PPI) network, respectively, as drugs targeting them may also have effects on other genes via co‐regulation and/or interaction and thus may have large efficacies.

Result

Using this strategy, we identified 389 genes, nearly half of which were not previously reported as AD‐associated. These genes explained large portions of heritability (47%‐97%). Sixty‐four genes were in the same co‐expression modules and/or PPI networks and 688 drugs targeting them were prioritized for further evaluation.

Conclusion

Gene‐based PRS is a cost‐effective way to identify AD‐associated genes using currently available data. Co‐expression modules and PPI networks can potentially identify drugs having large efficacy which can be further investigated for their potentials to treat AD.
Developing an anatomically valid segmentation protocol for early tau regions: the anterior medial temporal lobe cortices
Authors: Sadeghpour Niyousha , Ittyerah Ranjit , Denning Amanda E , Trotman Winifred , Lim Sydney A , Chung Eunice , Sadaghiani Shokufeh , Prabhakaran Karthik , Bedard Madigan L , Ohm Daniel T , Schuck Theresa , Artacho‐Perula Emilio , Martin Maria Mercedes Iniguez de Onzono , Munoz Monica , Romero Francisco Javier Molina , Gonzalez Jose Carlos Delgado , del Mar Arroyo Jimenez Maria , del Pilar Marcos Rabal Maria , Sanchez Sandra Cebada , de la Rosa Prieto Carlos , Parada Marta Corcoles , Insausti Ricardo , Wuestefeld Anika , McMillan Corey T , Grossman Murray , Lee Eddie B , Detre John A. , Trojanowski John Q , Tisdall Dylan M , Irwin David J. , Wolk David A. , Yushkevich Paul A. , Wisse Laura EM
Published: December 2023

Background

The anterior portion of the medial temporal lobe (MTL) is one of the earliest regions showing tau deposition in Alzheimer’s disease (AD) and hence a key focus area for AD imaging biomarkers. However, the anatomical variability of the anterior MTL presents a challenge for segmentation protocols. Leveraging a novel postmortem dataset with histology and MRI, we aimed to develop a histologically‐informed segmentation protocol for the anterior entorhinal cortex (ERC), Brodmann Area (BA) 35 (approximates transentorhinal cortex), and BA36 for in vivo 3 tesla (T) MRI.

Method

Digitized 50‐µm thick MTL Nissl‐stained coronal histology sections from 20 cases (Table 1) were annotated by expert neuroanatomists. Cases with and without neurodegenerative diseases were included to ensure broad generalizability of the protocol. The histology sections were registered to same‐subject 0.2×0.2×0.2‐mm3 9.4 T postmortem MRI and were analyzed together to determine the location of the histological borders of the MTL cortices in relation to anatomical landmarks observable on MRI.

Result

The distance between the anterior histological border of ERC, BA35 and BA36 was assessed in relation to different anatomical landmarks observable on MRI. The distance relative to the hippocampus was chosen, as there was relatively low between‐subject variability in distance (low SD in Table 2) and this region is easily identifiable on MRI. The ERC starts 4.75 mm (median) anterior to the hippocampus, BA35 9.25 mm and BA36 10.25 mm. There was no significant difference in distances between patients with and without neurodegenerative disease. Next, we analyzed the location of the ERC on histology sections. We determined that regardless of the depth of the collateral sulcus (CS) (contrary to more posterior regions), the inferior border of the ERC is on average at the edge of the CS and the superior border at the superior edge of the parahippocampal gyrus (Figure 1a), but at the halfway point for the first section with ERC. These segmentation rules for ERC can be applied to T1‐MRI (Figure 1b).

Conclusion

Segmentation rules for anterior BA35 and BA36 are under development. This histologically‐informed segmentation protocol is expected to improve the efficacy of imaging biomarkers for tau deposition in AD.
PRESYNAPTIC AMYLOID PRECURSOR PROTEIN IS NECESSARY FOR THE IMPAIRMENT OF SYNAPTIC FUNCTION AND MEMORY CAUSED BY EXTRACELLULAR AMYLOID‐ΒETA AND TAU OLIGOMERS
Authors: Acquarone Erica , Costa Ana Paula , de Loo Jonathan Van , Williams Damian , Zhang Hong , Staniszewski Agnieszka , D'Adamio Luciano , Puzzo Daniela , McIntire Laura Beth , Teich Andrew F , Arancio Ottavio
Published: December 2023

Background

Amyloid precursor protein (APP) is a transmembrane protein expressed at the synapse throughout life. In absence of APP, extracellular Aß‐ and tau‐oligomers no longer impair memory and its synaptic surrogate, long‐term potentiation (LTP). Synapses include pre‐ and post‐synaptic compartments. However, the relative role of pre‐ vs. post‐synaptic APP at the CA3‐CA1 hippocampal synapse in the Aß‐ and tau‐oligomer‐induced damage of memory and LTP is not know.

Method

We used a combination of gene editing, electrophysiological, behavioral and biochemical techniques to investigate the contribution of the pre‐ and post‐synaptic APP in oligomer induced impairment of memory and LTP.

Result

Specific ablation of APP expression in the post‐synaptic neuron did not alter the negative effects of Aß and tau oligomers on LTP and memory. In contrast, APP‐KO in the presynaptic neuron mimicked and occluded the negative effects of Aß and tau oligomers on LTP and memory, suggesting that presynaptic APP mediates the synapto‐toxic effect of Aß and tau. Further investigation demonstrated that pre‐synaptic APP deletion (but not post‐synaptic) mimicked and occluded the Aß and tau oligomer induced reduction of neurotransmitter vesicle availability during tetanic stimulation and increase of refilling rate after depletion of the readily‐releasable pool. Moreover, the increase in refilling rate after deletion of presynaptic APP was dependent upon intracellular calcium. Indeed, intracellular calcium homeostasis was affected both in basal conditions and after activity in full APP‐KO mice, likely due to decrease in the levels of inositol 1,4,5‐trisphosphate receptor, ryanodine receptor and the calcium pump, SERCA3.

Conclusion

These data support the view that Aß and tau oligomers affect synaptic function and memory through pre‐synaptic APP.
Are sex differences in verbal memory related to sex differences in cognitive reserve?
Authors: O'Shea Deirdre , Camacho Simone , Ezzeddine Reem , Disla Shanell , Galvin James E
Published: December 2023

Background

Cognitive reserve (CR) is the capacity to maintain cognitive performances despite underlying brain pathology and a concept used in Alzheimer’s disease (AD) studies to explain clinical heterogeneity. Evidence for a female‐specific verbal memory reserve may contribute to sex disparities in AD incidence, via delayed diagnosis. However, whether sex differences in verbal memory relate to sex differences in CR, is unclear. The current study examined whether multiple measures of CR differed by sex and whether they mediated sex differences in verbal memory.

Method

Cross‐sectional data from 59 older adults (mean age = 68.1; SD = 10.7; Female = 62%; White = 70%), without a prior diagnosis of cognitive impairment, were included. Total recall from the immediate and delayed recall trials of the scores Hopkins Verbal Learning Test (HVLT) were used to assess verbal learning and memory. Years of education, self‐reported leisure activities, physical activity, mindfulness, and the MIND diet were used to assess CR. Sex differences in HVLT scores were tested with ANCOVAs, controlling for age and reran adjusting for education. A MANCOVA was used to assess sex differences on CR measures. A mediation analyses was used to test whether sex differences in CR measures mediated the association between sex differences and verbal memory.

Result

Women had higher scores on HVLT learning (M = 23.1, SD = 5.2; p<.01), delayed recall (M = 8.2; SD = 2.6; p<.01) and leisure activities (M = 35.93; SD = 7.9; p<.01) compared to men (learning: M = 19.5; SD = 5.2; delayed recall: M = 6.2; SD = 2.5; leisure: M = 28.5; SD = 10.9; p<.01). No other sex differences in CR measures were revealed. Leisure activities fully mediated sex and HVLT associations, such that women’s higher scores on leisure explained 39% and 35% of the variance between sex and HVLT learning and delayed recall, respectively.

Conclusion

Women’s overall higher engagement in leisure activities accounted for their higher scores on HVLT learning and delayed recall relative to men. Increasing men’s engagement in leisure activities could attenuate sex differences in verbal learning/memory but warrants further investigation. Larger and more diverse samples are needed for follow‐up data analyses.
Integrated spatial and single‐cell transcriptomic analysis of genetic and sporadic forms of Alzheimer’s disease
Authors: Morabito Samuel , Miyoshi Emily , Henningfield Caden M , Shi Zechuan , Michael Neethu , Shabestari Sepideh Kiani , Das Sudeshna , Shahin Saba , Head Elizabeth , Green Kim N , Swarup Vivek
Published: December 2023

Background

The pathogenesis of Alzheimer’s disease (AD) varies greatly depending on environmental and heritable factors. Neuropathological scores aid in the understanding of disease severity in postmortem tissue, but fail to provide insights into disease onset and progression. Conversely, mouse models of AD like 5XFAD offer predictable timelines of amyloid accumulation due to specific human AD risk signals, but have limitations due to species differences. Studying AD in Down Syndrome (AD in DS) patients provides an opportunity to study the transcriptomics of AD progression due to overexpression of APP, which results in a more predictable disease time course compared to the more stochastic disease progression in the general population.

Method

We present a rigorous transcriptomic analysis of AD using single‐nucleus RNA‐seq (snRNA‐seq) and spatial transcriptomics (ST) in cortical samples from donors with early‐stage AD, late‐stage AD, AD in DS, and cognitively normal controls. We performed ST (10X Genomics Visium) in these groups, and additionally performed snRNA‐seq (Parse Biosciences) in tissue from AD in DS donors and controls. Finally, we profiled 5XFAD and wild type mice at four time points (4, 6, 8, and 12 months) using ST to facilitate cross‐species comparisons. We applied state‐of‐the‐art bioinformatic and statistical approaches to integrate these datasets with published AD snRNA‐seq data and to perform systematic analyses of gene expression and gene networks in these groups.

Result

We found shared and distinct differentially expressed genes (DEGs) between AD and AD in DS in the ST and snRNA‐seq datasets, with greater concordance in neuronal cell types compared to glia. Cell‐cell communication network analysis of integrated snRNA‐seq and ST data revealed vast network remodeling in disease, highlighting an increase in WNT and ANGPTL signaling and a decrease in CD99 signaling among other disrupted pathways. Using geospatial statistical analysis, we identified amyloid plaque proximal DEGs in human and mouse ST data, which were largely species‐specific with little overlap.

Conclusion

The primary data generated here will be a valuable resource for the AD community, and our study provides new insights into the transcriptomics of AD and amyloid pathology by performing a holistic analysis considering sporadic and genetic forms of AD.
Butyrylcholinesterase Kalow variant reduces age‐of‐onset of Alzheimer Disease in apolipoprotein ɛ4 carriers
Authors: Lane Roger M , Junge Candice , Li Dan , Yang Qingqing M , Moore Katrina M , Edwards Amanda , Graham Danielle , Mummery Catherine J
Published: December 2023

Background

Previous investigations suggest carrier status for Karlow‐variant single‐nucleotide polymorphism (SNP) of butyrylcholinesterase (BCHE‐K) is associated with an earlier age‐at‐onset of AD in APOE4 carriers.

Method

In 45 mild AD patients, 50‐74 years, recruited into a clinical trial (NCT03186989), baseline characteristics were evaluated by BCHE‐K and APOE4 allelic status. Hypothesis tested that age‐at‐diagnosis of AD in APOE4 carriers was lowered in BCHE‐K carriers. Exploratory investigations conducted of associations of neuroimaging (ventricular and hippocampal volumes) and CSF biomarkers of amyloid (Aβ42), tau (p‐tau181), and neurodegenerative (NfL, Ng, PSD‐95) pathologies and glial activation (YKL‐40, GFAP, MCP‐1) across gender and genotype subgroups.

Result

In APOE4 carriers (N = 33), mean age‐at‐diagnosis of AD in BCHE‐K carriers (N = 11) was 6.4 years earlier than in BCHE‐K non‐carriers (N = 22, p < 0.001). In APOE4 non‐carriers (N = 12) there was no similar influence of BCHE‐K, but men (N = 8) had an age‐at‐diagnosis about 11 years earlier than women (N = 4). In APOE4 carriers, accumulation of amyloid and tau pathologies was slightly greater and ∼6 years earlier in BCHE‐K carriers versus non‐carriers. APOE4 allele frequency‐dependent increase in amyloid pathology observed with highest amyloid burden in APOE4 homozygotes that contrasted with lowest tau burden. Multiple regression analyses demonstrated that factors associated with amyloid accumulation included APOE4 carrier status (p < 0.05), larger total brain ventricle volume (p < 0.05), less synaptic injury (PSD‐95, p = 0.01; Ng, p < 0.001), and less tau (t‐tau and p‐tau181, p < 0.01). Factors associated with tau pathology included higher neuroaxonal damage (NfL, p = 0.002), higher synaptic injury (Ng, p <0.001; PSD‐95, p < 0.001), and higher glial activation (YKL‐40, p = 0.01). Phenotypic spectrum observed from predominant amyloid and limbic‐amnestic, exemplified by APOE4 homozygotes with BCHE‐K, to predominant tau, limbic‐sparing and multi‐domain cognitive impairment, exemplified in older women non‐carriers of APOE4 and BCHE‐K.

Conclusion

In mild AD APOE4 carriers aged < 75 years, the mean age‐at‐diagnosis of AD was reduced by about 6 years in BCHE‐K carriers relative to non‐carriers. Relationships between biomarkers of amyloid and tau pathologies, neurodegeneration and glial activation, and putative cortical cholinergic denervation, suggested an age‐, gender‐ and genotype‐dependent phenotypic spectrum.