bluuebunny/crossref_metadata_2025 huggingface dataset:
Low‐Frequency Oscillations During Resting and Task Differentially Associate with Working Memory Performance in Older Adults
Authors: Venkatesan Tharunika , Fei Ellen , Hammond Tyler C , Zhao Xiaopeng , Thibault Olivier , Sompol Pradoldej M , Norris Christopher M. , Jicha Gregory A , Jiang Yang
Published: December 2023

Background

Increased intrinsic slow delta oscillations during resting state are associated with brain aging and increased Alzheimer’s disease/related dementia pathologies, i.e., synaptic network dysfunctions and astrocyte over‐reactivity in human (Wiseman et al., 2022) and animal models (Sompol et al., 2023). Here we examined the relations of working memory performance (accuracy and reaction time) with low frequency electroencephalogram (EEG) oscillations during resting and task.

Method

34 cognitively normal adults (26 female; mean age 77, education 17 years) from UK‐ADRC participated in the study. EEG was recorded using a wireless headset while participants performed a visual working memory task (Borhani et al., 2021), first using their dominant hand (DH, better cognitive motor) then using their nondominant hand (NDH) to indicate a working memory target. Additionally, they participated in resting state eyes closed (EC) and eyes open (EO) pre‐ and post‐task (Fig. 1). EEG data was cleaned and extracted for frequency power using a program developed by Zhao Lab. Pearson correlations were applied.

Result

Under EC resting state, longer reaction times (during retrieval of memory target) positively correlated with increased Delta power in the left frontal site (FC5) during pre‐task (0.34) and the left parietal site (P7) during post‐task (0.35) (Fig. 2). In contrast, increased Theta power in the left frontal site (F3) associated with faster reaction times (‐0.32) during pre‐task EC.

Under EO and the task, shorter reaction times negatively correlated with increased Delta power at F3 during post‐task EO (‐0.31) (Fig. 3) and the right frontal site (F4) during task NDH (‐0.33). At P7 (0.31) and F3 (0.32), increased Delta positively correlated with higher retrieval accuracy during pre‐task EO. Conversely, longer reaction times at F4 during task NDH (0.30) and decreased accuracy at P7 during pre‐task EO (‐0.31) correlated with increased Theta.

Conclusion

Increased intrinsic slow Delta (0.5‐3.5 Hz) during eyes closed is associated with longer working memory retrieval time but during eyes open or task correlates with faster reaction times. Increased Theta power (4‐7 Hz) showed opposite relations with working memory performance compared to Delta power. Low frequency neural slowing has emerged as promising indicators of pathophysiological changes during brain and cognitive aging.
FDA‐approved carbonic anhydrase inhibitors rescue brain Aβ overload, cerebrovascular pathology and gliosis in Alzheimer’s disease model
Authors: Canepa Elisa , Vazquez‐Torres Rafael , Guzman‐Hernandez Roberto A , Debure Ludovic , Angiulli Federica , Parodi‐Rullan Rebecca M , Lemon Nicole L , Fossati Silvia
Published: December 2023

Background

Most of Alzheimer’s disease (AD) cases present cerebrovascular dysfunction (CVD) and neuroinflammation, at both early and late stages of AD progression. Dysfunctional vasculature and glial cells favor Aβ deposition, inducing brain cell stress, neuroinflammation, impaired clearance/ metabolic waste accumulation, blood‐brain barrier permeability, and ultimately leading to neurodegenerative processes and cognitive impairment. Endothelial cells (ECs) and microglial cells are major players in mediating vascular and glial fitness, and therefore clearance and inflammatory response. Our previous findings in vitro demonstrated that Aβ elicits mitochondrial dysregulation and caspase‐mediated apoptosis in ECs and glial cells. We also showed that FDA‐approved carbonic anhydrase inhibitors (CAIs), acetazolamide (ATZ) and methazolamide (MTZ), employed in non‐AD related conditions, hinder these pathological events.

Method

TgSwDI mice, expressing human Amyloid‐β Precursor Protein, APP, carrying the Swedish, Dutch and Iowa mutations, were employed as AD/CAA (Cerebral Amyloid Angiopathy) model. The model is characterized by fibrillar Aβ burden in the cerebral microvasculature and in the parenchyma, starting at 6 months, as well as abundant gliosis. 8‐month‐old Tg animals were fed 8‐month‐CAI‐diet, following which we harvested the brains for biochemical and immunohistochemical assessments.

Result

CAIs significantly reduced brain amyloidosis, and vascular and microglial Aβ accumulation. In addition, CAIs prevented caspase‐3 activation in ECs and microglia, ameliorating vascular and glial fitness, as we observed less microhemorrhages, reduced microgliosis, and microglial pro‐clearance phenotype. We also unveiled a critical novel druggable target, showing that the mitochondrial isozyme Carbonic Anhydrase (CA)‐VB is specifically upregulated in human cerebral endothelial and microglial cells challenged by Aβ, and most importantly is overexpressed in TgSwDI mouse brains, and in human brains of CAA and AD (with CAA) patients.

Conclusion

CAIs promote vascular health, glial anti‐inflammatory/pro‐healing phenotype and Aβ phagocytosis, which may underlie Aβ deposition reduction. This work paves the way for the application of CAIs in clinical trials for AD and CAA, and uncovers CA‐VB as a mediator of cerebral Aβ toxicity in endothelial and microglial cells.
Gut microbial composition mediates the relationship between intestinal inflammation and amyloid burden before cognitive decline
Authors: Heston Margo B. , Hong Qilin , González Antonio , Betthauser Tobey J , Chin Nathaniel A. , Hanslik Kendra L. , Zarbock Katie R , Kerby Robert L. , Asthana Sanjay , Johnson Sterling C , Knight Rob , Kaddurah‐Daouk Rima F. , Tang ZhengZheng , Ulland Tyler K. , Rey Federico E. , Bendlin Barbara B
Published: December 2023

Background

Gut microbial composition is associated with Alzheimer’s disease (AD) pathology, and recent findings (Heston et al, medRxiv 2022) have identified an increase in intestinal inflammation with greater age and with higher cortical amyloid burden. Although gut microbiome composition and intestinal inflammation have independently been linked to AD pathology, it remains unclear whether the microbiome and gut inflammation are interrelated in the context of preclinical AD. Here we used phylogenetically‐based mediation (PhyloMed) to test whether the gut microbiome mediates the relationship between gut inflammation and cortical amyloid burden, and to highlight bacterial clades that may be specifically implicated as mediators.

Method

78 participants (Table 1) were enrolled in the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention, collected fecal samples, and completed C11‐PiB PET. Figure 1 illustrates the processing and analysis for each data stream. Fecal calprotectin was measured to quantify intestinal inflammation, and 16S rRNA sequencing characterized the fecal microbiome. Testing the full cohort and the cognitively unimpaired (CU) subset separately (n = 73), PhyloMed was performed at every taxonomic level, resulting in 14 models. Covariates included age, sex, body mass index, Bristol Stool Scale score, cognitive diagnosis/amyloid status, pseudocontinuous APOE AD risk score, and age difference between PET scan and fecal sample.

Result

For both the full and CU cohorts, models at the amplicon sequence variant (ASV) level showed that gut microbiome composition was a significant mediator (p<0.05); species‐ and genus‐level models were marginally significant (p<0.1, Benjamini‐Hochberg FDR) (Table 2). ASVs from the family Lachnospiraceae (Figure 2A) were highlighted as significantly mediating taxa (p<.05, FDR). Interestingly, these taxa were negatively associated with calprotectin, while they were positively associated with PiB DVR (Figures 2B, 2C).

Conclusion

Even before cognitive decline, the gut microbiome mediated the relationship between calprotectin, a measure of gut inflammation, and cortical PiB DVR, a measure of amyloid burden. Taxa within Lachnospiraceae were implicated as specific mediators, linked with lower inflammation and higher amyloid burden. Future work will use germ‐free mouse models to functionally elucidate the role of these bacteria in inflammation and AD.
Genome‐wide association meta‐analysis of plasma neurofilament light levels in high‐risk adults with Down Syndrome
Authors: Dang Lam‐Ha T , Petersen Melissa , Xicota Laura , O'Bryant Sid E. , Krinsky‐McHale Sharon J , Mapstone Mark , Kamboh M. Ilyas , Cruchaga Carlos , Handen Benjamin L. , Pang Deborah , Silverman Wayne , Schupf Nicole , Lee Joseph H.
Published: December 2023

Background

Only a few studies in the general population have investigated genetic contributions to variation in levels of neurofilament light (NfL), which is a general marker of axonal damage and is predictive of Alzheimer’s disease (AD). To our knowledge, no studies have examined this relation in people with Down Syndrome (DS), a population at high risk of developing AD. We performed a genome‐wide search for SNPs associated with plasma NfL levels. We paid special attention to genetic variants identified in the general population to be associated with AD risk and NfL to evaluate whether those variants contributed to AD in DS by altering NfL levels.

Methods

We performed a meta‐analysis using two datasets (N = 455): the omicsADDS and ABC‐DS studies. Levels of plasma NfL were measured using the Simoa platform and genotyping was performed using an Illumina Infinium General Screening Array v2. Imputation on autosomal chromosomes other than 21 was performed using the TOPMed Imputation Server. We first assessed the association between SNPs and plasma NfL levels in each dataset using a multivariable linear regression model that included age, sex, dementia status, and genetic ancestry. We then performed meta‐analysis using sample size weighting. We restricted our meta‐analysis to variants that had study‐specific P<5×10−4, to minimize potential false positives.

Results

Our genome‐wide scan, after Bonferroni correction, identified 33 novel SNPs contributing to variation in plasma NfL (28 variants with elevated plasma NfL and 5 variants with decreased plasma NfL). Three AD‐risk variants previously identified in the general population (UNC5CL/rs10947943, USP6NL/rs7912495, FOXF1/rs16941239), were found to be associated with variation in plasma NfL levels at nominal Pmeta < 0.05. Candidate variants associated with NfL in the general population were not replicated in the current meta‐analysis. The novel genes identified have been implicated in tau neuropathology, variation in lipid levels, insulin regulation, and neurotransmitter release.

Conclusion

This genome‐wide meta‐analysis revealed multiple novel genetic loci associated with NfL levels in plasma in adults with DS. We additionally found supporting evidence for three known variants. The genes identified here may lead to insight into underlying mechanisms of neurodegeneration and AD in adults with DS.
Using neuroimaging biomarkers to define plasma thresholds in a community dwelling cohort
Authors: Rudolph Marc D. , Sutphen Courtney L. , Register Thomas C. , Whitlow Christopher T. , Sai Kiran K. Solingapuram , Hughes Timothy M. , Bateman James R. , Dage Jeff L. , Russ Kristen A. , Mielke Michelle M. , Craft Suzanne , Lockhart Samuel N.
Published: December 2023

Background

AD Imaging biomarkers (IBM) include measures of amyloid (A) on PET, and neurodegeneration (N) on MRI, with thresholds for classification of imaging A/N positivity commonly used at research centers. Novel AD plasma biomarkers (PBM) can potentially enhance neuropathological characterization; however, knowledge regarding which thresholds to use to characterize PBM abnormalities is limited.

Method

We evaluated a range of PBM thresholds based on (1) plasma data alone (gaussian mixture models [GMM]), and (2) when classifying A/N IBM using both existing and data‐driven cutoffs (ROC analyses). Baseline plasma and imaging data were obtained in a community‐dwelling cohort enrolled in the Wake Forest ADRC, including cognitively normal participants (N = 300) and individuals with consensus diagnosis of mild cognitive impairment (N = 192) or dementia (N = 64; Table 1). We examined PBMs (Quanterix SIMOA HD‐X from NCRAD: Aβ42/40, GFAP, NfL, p‐tau181) and IBM measures of A (global PiB PET; A+>1.21 SUVR) and N (FreeSurfer temporal cortical thickness; MAYOTHCK), N+≤2.68mm; FreeSurfer hippocampal volume, N+≤0.454% head size; HPC‐VOL).

Results

Optimal/low/high GMM‐derived thresholds based on PBM distributions (Figure 1a) are provided in Figure 1b. ROC analysis using existing IBM cutoffs are in Figure 1c, with details (sensitivity/specificity/AUC) in Figure 1d. GMM‐ and ROC‐derived p‐tau181 thresholds were highly aligned (range 3.698‐4.071 pg/ml). For NfL and GFAP, imaging ROC‐derived thresholds were lower than GMM‐derived thresholds. AUCs were highest when PBM classification was used to predict A‐PET using existing PET‐positivity cutoffs, with PBM performing more poorly for MRI‐based cutoffs. A/N IBM histograms and current/optimal/low/high GMM‐derived thresholds for each IBM are in Figure 2a. Figure 2b represents how different data‐driven IBM cutoffs impact PBM thresholds in ROC analyses, with AUC statistics for these ROC analyses in Figures 2c‐e. Notably, GMM‐optimal IBM cutoffs performed similarly to current cutoffs for defining PBM thresholds, especially when using A‐PET (AUCs for current and GMM‐optimal >0.747).

Conclusion

While use of existing and data‐driven IBM cutoffs to define PBM thresholds in a community‐dwelling cohort is feasible, some plasma assays (e.g., p‐tau181) are more consistent than others, and caution is warranted against selecting a single threshold. To facilitate clinical use, future work will focus on establishing confidence intervals for PBM abnormalities.
Novel systemic delivery of a peptide‐mediated anti‐sense oligonucleotide to reduce α‐synuclein in a mouse model of Alzheimer’s Disease
Authors: Leitao Andre Direito Goulart , Spencer Brian , Wu Chengbiao , Masliah Eliezer , Rissman Robert A
Published: December 2023

Background

Neurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α‐synuclein (α‐syn) and amyloid beta (Aβ). Misfolded and aggregated α‐syn has been implicated in neurological disorders such as Parkinson’s disease (PD), and Dementia with Lewy Bodies (DLB), but less so in Alzheimer’s Disease (AD). However, accumulation of α‐syn has been confirmed in over 50% of postmortem brains of AD patients. To date, no therapeutic strategy has consistently downregulated α‐syn in AD.

Method

Here we tested the hypothesis that using a peptide (ApoB11) that binds a modified antisense oligonucleotide (2’‐O‐methyl si α‐syn or 2’‐OMe) for transport across the blood‐brain barrier following systemic administration, would downregulate α‐syn expression in an AD mouse model and improve behavioral and neuropathologic phenotypes. We tested the efficacy of the ASO in knocking down α‐syn both in vitro, using neuronal cell lines, and in vivo by measuring α‐syn levels in brains of treated mice with 2mg/kg at 6, 7 and 8 months of age.

Result

We found that treatment of APP transgenic mice with systemic delivery of ApoB11:ASO‐α‐syn reduces expression of α‐synuclein in specific regions of hippocampi of 9 month‐old APP transgenic mice. Downregulation of α‐syn led to a significant reduction of Aβ plaques burden, rescued neuronal loss and prevented astrogliosis, as compared to untreated PSAPP mice. Importantly, we found that AD mice treated with the ASO‐syn had greatly improved hippocampal and spatial memory function as shown by Morris Water Maze tests.

Conclusion

Collectively, the data shown in this work supports the use of ApoB11:ASO α‐syn conjugates delivered systemically to downregulate α‐syn as a promising future therapeutic strategy in AD. Our work suggests that knocking down α‐syn could be necessary to prevent neuropathology and prevent spatial memory loss.
Investigating mechanisms of sporadic progressive supranuclear palsy in autopsy‐validated human iPSC‐derived midbrain organoids and human brain tissue
Authors: Whitney Kristen R. , Krassner Margaret M. , Delica Sean Thomas , Farrell Kurt W. , Kim SoongHo , Dangoor Diana K. , Sharma Abhijeet , Song Won‐Min , Christie Thomas D. , Iida Megan A , Walsh Hadley A. , Sarrafha Lily , Parfitt Gustavo , Walker Ruth H. , Riboldi Giulietta M. , Frucht Steven J. , Ahfeldt Tim , Zhang Bin , Pereira Ana C. , Temple Sally , Crary John F.
Published: December 2023

Background

Progressive supranuclear palsy (PSP) is the most common primary tauopathy, with a constellation of pathological features including 4R‐tau positive neurofibrillary tangles and tufted astrocytes. Most PSP cases are sporadic and associated with common structural variation in the 17q21.31 MAPT locus as well as other risk loci, including EIF2AK3 which is critical for the unfolded protein response (UPR). Despite these known genetic risk associations, mechanisms underlying disease pathogenesis are unclear. To investigate candidate mechanisms, there is a critical need for model systems that better recapitulate the cellular complexity of the human brain. Human induced pluripotent stem cell (hiPSC) patient‐derived organoid models have emerged as powerful tools to study molecular and cellular changes in a disease‐relevant genomic context.

Method

Fibroblasts grown from sporadic PSP patient skin cells were cultured in vitro and reprogrammed into hiPSCs. HiPSC‐derived midbrain organoids were generated in suspension spinner flasks through pharmacological directed differentiation, processed and screened for patterning using qRT‐PCR, immunohistochemistry (IHC), and quantitative immunoblot. Total tau, tau isoform, hyperphosphorylated tau (p‐tau), and UPR activation markers were assessed in organoids and human brain tissue. Single‐nucleus RNA sequencing (snRNA‐seq) was performed on the subthalamic nucleus and adjacent structures in autopsy‐validated PSP brain tissue and clinically normal controls.

Result

PSP and control organoids displayed a cytoarchitectural and gene expression pattern consistent with the developing neuroectoderm and midbrain. We observed disease‐relevant differences between PSP and control organoids, including increased high molecular weight p‐tau, a higher ratio of p‐tau:total tau, and increased levels of 4R‐tau in the PSP organoids. Human PSP brain snRNA‐seq data showed dysregulation of the UPR in astrocytes and neuronal subpopulations. We also observed different UPR activation levels in PSP organoids. These findings were validated by neurohistological characterization of the UPR in autopsy brain tissue.

Conclusion

Single nucleus transcriptomic and neurohistological data reveals dysregulation of the UPR in key cell types affected in PSP. PSP patient‐derived organoids develop a characteristic midbrain cellular composition and recapitulate key disease‐relevant features, including elevation of toxic tau proteoforms and UPR dysregulation. This sporadic PSP organoid model will provide insight into cell‐type specific drivers of neurodegeneration that underlie sporadic tauopathy.
Association Between HSV‐1 and Risk of Alzheimer’s Disease Detected by a Propensity‐Score Matched Case Design
Authors: Tejeda Marlene , Farrell John , Zhu Congcong , Wetzler Lee , Lunetta Kathryn L. , Bush William S. , Martin Eden R. , Wang Li‐San , Schellenberg Gerald D. , Pericak‐Vance Margaret A. , Haines Jonathan L. , Farrer Lindsay A. , Sherva Richard
Published: December 2023

Background

Herpes simplex virus 1 (HSV‐1) is a neurotropic and neuroinvasive species that can enter the brain triggering inflammation and an immune response, increasing the risk of Alzheimer disease (AD). Previously, we found a significant association between HSV‐1 and AD in whole‐exome sequencing (WES) data (OR = 3.69, P = 6.71×10−4) but not whole‐genome sequenced (WGS) data (OR = 0.92, P = 0.27) from the AD Sequencing Project (ADSP).

Method

To understand this discrepancy, and to better control for the numerous covariates and technical differences that influenced viral quantity, we created a novel algorithm using propensity score analysis (PSA) which permits analysis of observational study data comparable to a randomized controlled trial. WGS reads from 6,541 AD cases and 6,855 controls from the ADSP (including 7,395 non‐Hispanic Whites, 2,961 African Americans, and 3,040 Caribbean Hispanics) that did not align to the human genome were mapped to viral reference sequences and quantified. Propensity scores were derived for 7,619 individuals with at least one HSV‐1 read and 5,777 individuals lacking any HSV‐1 reads using a binary treatment indicator for HSV‐1 status. We applied forward stepwise regression including known confounders (APOE ε4 status, sex, age, tissue source (blood or brain), population ancestry, sequencing center, and PCR amplification) to identify other potential confounders and/or interactions and quadratic terms for creating propensity scores. We tried several matching algorithms to generate matched sets of individuals with and without HSV‐1. Utilizing the best quality matched set, we evaluated the association of AD with HSV‐1 status using a weighted generalized linear model.

Result

The final regression model included terms for the covariates mentioned above that were available for most of the original sample (5828 AD cases and 6487 controls). We found a significant association between HSV‐1 and AD (OR = 1.10, P = 0.02).

Conclusion

Results from WGS data confirm our previous findings obtained from WES data and support the hypothesis that HSV‐1 is associated with an increased AD risk, highlighting the utility of PSA for analyzing association of risk factors with complex disorders like AD. Further studies are needed to replicate this finding in other ancestral populations and explain the lack of association in WGS data.
Atypical Alzheimer’s disease: new insights into an overlapping spectrum between the language and visual variants
Authors: Singh Neha Atulkumar , Graff‐Radford Jonathan , Machulda Mary M. , Carlos Arenn Faye , Schwarz Christopher G. , Senjem Matthew L. , Jack Clifford R. , Lowe Val J. , Josephs Keith A , Whitwell Jennifer L
Published: December 2023

Background

The language and visual variants are two common clinical phenotypes of atypical Alzheimer’s disease (AD). There are reports of overlap between these clinical phenotypes, however, the extent and frequency of overlap, and its neuroanatomical underpinnings remain unclear.

Method

Eighty‐two patients with biomarker‐confirmed AD who presented with either predominant language (n = 34) or visuospatial/perceptual (n = 48) deficits were recruited by the Neurodegenerative Research Group and underwent neurological and neuropsychological testing, MRI and [18F]flortaucipir‐PET. The clinical examination included testing for simultanagnosia, Gerstmann’s syndrome, ideomotor apraxia, visuospatial‐visuoperceptual function, confrontational naming, sentence repetition and letter and animal fluency. Cut‐points for abnormality were defined for each test and used to classify the following groups: language‐pure (no visual‐function deficit), language‐plus (impaired on one visual‐function), language‐mixed (impaired on two visual‐functions), visual‐pure (no language‐function deficit), visual‐plus (impaired on one language‐function) and visual‐mixed (impaired on two language‐functions). Patterns of relative volume loss and flortaucipir uptake were assessed using SPM12.

Result

Of the 82 patients, 11 (13%) were language‐pure, 16 (20%) language‐plus, 7 (8%) language‐mixed, 10 (12%) visual‐pure, 17 (21%) visual‐plus and 21 (26%) visual‐mixed, with no difference in disease duration across groups. Visual deficits in the language‐plus group consisted of mild simultanagnosia in 29%, Gerstmann’s syndrome in 24%, and mild visuospatial deficits. In the language‐mixed group 86% had simultanagnosia and 43% had Gerstmann’s syndrome, with visuospatial‐visuoperceptual deficits comparable to the visual‐pure group. Language deficits in the visual‐plus group consisted of mild anomia and reduced letter and animal fluency. The visual‐mixed group reported naming and repetition deficits, and reduced fluency, comparable to the language‐predominant groups. All three language groups showed left temporal volume loss and flortaucipir uptake, with greater involvement of the parieto‐occipital and frontal lobes in language‐plus and language‐mixed groups. All three visual groups showed occipital volume loss and flortaucipir uptake, with greater involvement of the parieto‐temporal and frontal lobes in visual‐plus and visual‐mixed groups.

Conclusion

Only 25% of our cohort showed a pure language or visual presentation, highlighting the high frequency of syndromic overlap in atypical AD and the diagnostic challenge of categorical phenotyping. Syndromic overlap was associated with neuroanatomical overlap and more widespread patterns of atrophy and tau deposition.
Evaluation of biomarker, behavioral, and immunostimulatory profiles following treatment with Class C CpG ODN in a non‐human primate model of sporadic CAA
Authors: Patel Akash G , Karimi Sohail , Nehete Pramod N , Nehete Bharti P , Murray Sean , Debure Ludovic , Soliman Muhammad T , Szabo Jakub , Levine Dafna T , Williams Lawrence E , Gray Stanton B , Hopkins William D , Wisniewski Thomas , Scholtzova Henrieta
Published: December 2023

Background

Innate immunomodulation has shown potential to be an effective therapeutic approach in ameliorating pathological features of Alzheimer’s Disease (AD). Our recently published study showed a reduction in cognitive deficits and AD‐related pathology in a squirrel monkey model (SQM) of sporadic cerebral amyloid angiopathy (CAA) following treatment with TLR9 agonist, Class B CpG ODN. Subsequently, we commenced a chronic treatment study evaluating the efficacy and safety of Class C CpG ODN in geriatric SQMs. Here, we further explore the efficacy of Class C CpG ODN by evaluating fluid biomarkers and implementing automated cognitive tests. Moreover, we assess the immunostimulatory profiles induced by Class B and Class C CpG ODNs using RNA‐Seq genome‐wide transcriptome analysis of SQM PBMCs.

Method

Geriatric SQMs received monthly injections of CpG ODN‐C or saline (VEH) over three years. Fluid biomarkers for cerebrovascular dysfunction, neurodegeneration, and neuroinflammation were assessed by Luminex and SIMOA. Touchscreen‐based Automated Cognitive Testing System (ACTS) was applied among socially living SQMs to assess behavioral changes. RNA‐Seq analyses were performed using PBMCs isolated 24hrs following CpG ODN‐B and ‐C administrations in a separate cohort of elderly SQMs.

Result

Our initial experiments confirmed the utility of SQMs for investigating plasma age‐associated neurodegeneration biomarkers, including NfL, GFAP, and neurogranin. Preliminary evaluation of cerebrovascular dysfunction‐related plasma biomarkers, such as MMPs, albumin index, bFGF, and VCAM, revealed no differences between our treatment groups at earlier time points. Although not significant, higher levels of plasma sTREM2 and YKL‐40 were observed in VEH monkeys compared to CpG ODN‐treated group. Concluding assessments will be performed in plasma collected at the end of the treatment period. Characterization of additional plasma/CSF biomarkers related to AD/neurodegeneration is underway. ACTS‐based two‐choice discrimination learning task revealed that CpG ODN‐treated group performed with a greater correct response rate than the VEH group. As expected, RNA‐Seq analyses of SQM PBMCs revealed significantly altered pathways, including Th1/Th2, TLR signaling, phagocytosis, chemokine signaling, interferon signaling, and senescence pathways, in addition to pathways involved in infiltration, activation, and recruitment of various immune cells.

Conclusion

The study highlights the potential of the SQM model for future translational research on CAA/AD and for advancing innovative therapeutic interventions.
Does the Timing of Alzheimer’s Disease vary by Severity of Intellectual Disability in Down Syndrome?
Authors: Fleming Victoria L , Hartley Sigan , Handen Benjamin L. , Tudorascu Dana , Lee Laise , Krinsky‐McHale Sharon J , Hom Christy , Cohen Annie , Schworer Emily K , Peven Jamie C , Zammit Matthew D , Klunk William E , Laymon Charles M , Zaman Shahid , Ances Beau , Christian Bradley T. ,   the Alzheimer’s Biomarker Consortium‐Down Syndrome
Published: December 2023

Background

Trisomy 21 causes Down syndrome (DS) and is a recognized cause of Alzheimer’s disease (AD). The triplication of the amyloid precursor protein gene leads to an overexpression of amyloid‐beta (Aβ), which accumulates into extracellular plaques, followed by intracellular neurofibrillary tau tangles (Lott & Head, 2019). However, variability in the age of AD onset in DS spans 25+ years (Iulita et al., 2022). As the DS field moves to AD clinical trials, it is important to identify factors related to this variability, such as premorbid severity of intellectual disability (ID). We compared the age‐trajectory of the AD biomarkers Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type (full, mosaic, translocation) and APOE status

Method

Analyses involved 361 adults with DS (M = 45.22 years, SD = 9.92) from the Alzheimer’s Biomarkers Consortium‐Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was recorded. PET was acquired using [11C] PiB for Aβ, and [18F] AV‐1451 for tau in 162 participants. Aβ was quantified using the centiloid method and tau was quantified as SUVR (reference: cerebellar cortex) in a composite region determined as the volume‐weighted average of select FreeSurfer 5.3, T1 MR‐based components.

Results

General linear models controlling for site, age, trisomy type and APOE status indicated no significant effect of premorbid ID level by age on the cognitive outcomes (Figure 1a‐e). There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET (Figure 2a‐b). There was not a significant difference in age of those with mild cognitive impairment‐DS (MCI‐DS) or dementia by premorbid ID level (Figure 3).

Conclusion

This study adds to the characterization of the time course of AD pathology and clinical symptomology in DS. Findings provide robust evidence of a similar time course in AD trajectory across severity of ID, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials. Premorbid IQ may have little effect on AD biomarkers in DS in contrast to findings in neurotypical populations.
The Contribution of Hyperhomocysteinemia to Aβ‐Induced Endothelial Cell Apoptosis, Blood Brain Barrier Dysfunction, and Angiogenic Deficits
Authors: Carey Ashley M , Parodi‐Rullan Rebecca M , Fossati Silvia
Published: December 2023

Background

Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimer’s Disease (AD) pathology, with particularly endothelial cell (EC) stress promoting the focal ischemia, cerebral blood flow impairments, and blood brain barrier (BBB) permeability that are pathologically characteristic in AD. Recent evidence has emerged suggesting a link between cardiovascular (CV) diseases and AD pathology, particularly showing that CV/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), contribute to AD pathology and risk. Despite this, the underlying molecular mechanisms for this interaction remain unclear. Previously, our lab has demonstrated that amyloid beta (Aβ), particularly Aβ40‐Q22 (the vasculotropic Dutch mutant), promotes TRAIL death receptor (DR)‐mediated apoptosis, barrier permeability, and angiogenic impairment within human cerebral ECs. We tested the hypothesis that Hhcy exacerbates Aβ‐induced cerebral EC TRAIL DR‐mediated apoptosis, barrier dysfunction, and angiogenesis defects.

Method

Human cerebral microvascular ECs (HCMECs) were challenged with AβQ22 and/or homocysteine (Hcy). Apoptotic mediator expression, caspase activation, cytochrome c release, and DNA fragmentation were measured to assess apoptosis. Junction protein expression, trans‐endothelial‐electrical‐resistance (TEER), and inflammatory mediators were measured to assess EC barrier integrity. Angiogenesis inhibition and activation (cytokine expression, pVEGFR2Y1175 expression/localization, VEGF‐A ELISA) assays were utilized to measure EC angiogenic capability and wound healing and actin polymerization assays were utilized to measure EC wound healing ability.

Result

Combined challenge of ECs with AβQ22 and Hcy potentiated increases in TRAIL DR‐related apoptotic mediators' expression, caspase activity, cytochrome c release, and DNA fragmentation and potentiated decreases in anti‐apoptotic mediators’ expression at differential timepoints. Treatment of ECs with AβQ22 and Hcy additively decreased TEER and, at certain timepoints, potentiated decreased junction protein expression, increased inflammatory mediator expression, and phosphorylated BBB protein expression. Combined treatment of ECs with AβQ22 and Hcy additively decreased angiogenesis progression, angiogenesis‐stimulating cytokine expression, wound healing capability, and actin polymerization levels. Additionally, Hcy decreased HCMEC soluble VEGF‐A levels.

Conclusion

The presence of high Hcy exacerbates Aβ induced‐EC apoptosis, barrier dysfunction, and angiogenic impairment. This study revealed several of the specific molecular mechanism through which amyloidosis and CV risk factors may additively act to produce EC dysfunction and death in AD.
The Sustainable Personalised Interventions for Cognition, Care, and Engagement (SPICE) Program: A twelve week reablement intervention for people with dementia and carers
Authors: D'Cunha Nathan M , Bennett Michelle , Mitterfellner Rachael , Brennan Rosalie , Wiseman Lara , Isbel Stephen , Bail Kasia , Barrett Louise , Rutherford Kathleen , Huang Ian , Gibson Diane
Published: December 2023

Background

There is a need for integrated and effective reablement programs to promote the quality of life of people with dementia and their carers.

Method

The Sustainable Personalised Interventions for Cognition, Care, and Engagement (SPICE) Program is currently being evaluated in Canberra, Australia. SPICE is a multicomponent active therapeutic intervention delivered by allied health professionals over twelve weeks. The five components are: 1) cognitive stimulation therapy (CST); 2) carer education, support and capacity building; 3) physical activity; 4) Care of People with dementia in their Environments (COPE) program; and 5) dietary assessment and advice. Six people with dementia and their six carers participate in a small group twice per week for the CST, carer, and physical activity components, while COPE and dietary assessment and advice are completed as a dyad. Pre‐ and post‐intervention outcome measures on quality of life, neuropsychiatric symptoms, cognitive function, and physical function are being collected, in addition to a program evaluation interview. After four groups have completed the protocol, the SPICE waiting‐list pilot trial will finish data collection in early 2024. Here we report on the first group to complete the program.

Result

Attendance to the in‐person components of the program were 94% for people with dementia and 92% for carers. All participants completed the COPE program, and compliance with the dietary appointments was 94%. Quantitative outcome measures suggest benefits, but inferences cannot be drawn due to small sample size. Both people with dementia and carers reported high program satisfaction and perceived benefits, supporting the feasibility of the intervention. The program was rewarding for all participants, and carers felt the strategies and lessons learned had immediate benefits. The social aspects, inclusiveness, and group cohesiveness were key drivers of their satisfaction with the program.

Conclusion

The results from the first group to complete the SPICE program shows that an intensive, multicomponent active therapeutic program is feasible and considered valuable for people with dementia and their carers. Findings from the pilot trial are required to confirm the results from the first group to potentially support a randomised controlled trial.
Regulation of tau‐phosphorylation and other Alzheimer’s disease‐associated phenotypes in REST conditional knockout mice
Authors: Tomás Mariana Santos Vidal , Benestad Johan Lafond , Keime Céline , Buckley Noel , Beglopoulos Vassilios
Published: December 2023

Background

The RE1‐silencing transcription factor (REST) has been strongly implicated in Alzheimer’s disease (AD), healthy ageing and longevity, and there is a clear need to understand better the exact mechanisms that mediate that role. Here we study the role of REST in a series of AD‐related phenotypes in the mouse brain.

Method

We have previously generated a conditional knockout (cKO) mouse model, lacking Rest in the postnatal forebrain. Immunohistochemistry and Western blot were used to evaluate the effect of REST on neuronal, synaptic and astrocytic markers and key proteins involved in tau phosphorylation. Furthermore, RNA‐Seq (including gene ontology, gene set enrichment and protein‐protein interaction analyses) was used to study the effect of REST inactivation at the transcriptome.

Result

Quantification of labelled neuronal nuclei on brain sections revealed no major neurodegeneration in Rest cKO mice. However, mild phenotypes of dendritic degeneration and as astrocytic activation were suggested. The levels of an important postsynaptic protein, PSD‐95, appeared reduced in the brain of Rest cKO mice. Interestingly, levels of proteins involved in the phosphorylation of tau, such as glycogen synthase kinase‐3beta (GSK‐3β) and p35/p25 (activators of CDK5), as well as the levels of phosphorylated tau, were found increased in the brain of Rest cKO mice. RNA‐seq results suggest that postnatal inactivation of REST down‐regulates synaptic activity and neuronal pathways, while triggering an immune response.

Conclusion

Our results suggest dysregulation of one of the biochemical hallmarks of Alzheimer’s disease, tau phosphorylation, and of synaptic and neuronal pathways, as well as an immune response, when REST is inactivated in the adult mouse brain.
Psychometric Characteristics of the Novel Subjective Cognitive Changes Questionnaire (SCC‐Q) in Older Adults at Risk of Dementia
Authors: Zuntychová Terezie , Vyhnalek Martin , Matuskova Veronika , Krejčová Svatava , Laczó Jan , Hort Jakub , Markova Hana
Published: December 2023

Background

Subjective cognitive complaints (SCC) in the elderly may represent an early cognitive marker of Alzheimer’s disease (AD). Currently, there is no recommended gold standard for evaluating SCC. In addition, available questionnaires were originally developed to identify individuals at later stages of AD. Based on previous research, we constructed the Subjective Cognitive Changes Questionnaire (SCC‐Q), which includes items potentially sensitive to early cognitive decline. The study aimed to analyse reliability of the individual items and construct and convergent validity of the SCC‐Q.

Method

A total of 211 non‐demented participants over the age of 55 from the Czech Brain Aging Study (CBAS) underwent a comprehensive neuropsychological examination, based on which they were classified into two groups: patients with amnestic mild cognitive impairment (n = 88) and those with subjective cognitive decline (SCD) (n = 88). Further, we included cognitively healthy volunteers without SCC (n = 35). All participants completed the novel 26‐item SCC‐Q in which they evaluated change in specific cognitive abilities during the last 5 years on a 5‐point Likert scale. The structure of the SCC‐Q was explored using the principal component analysis (PCA) with varimax rotation. To analyse associations between the components and cognitive performance (convergent validity), non‐parametric partial rank correlations controlled for sex, age and education were performed. Cognitive performance was expressed as composite z‐scores representing memory, attention and working memory, language, executive, and visuospatial function.

Result

Item analysis showed that all included items were highly reliable (McDonald’s Ω > 0.9, Cronbach’s α > 0.9). Using the PCA, four components explaining 57.6% of the variance were identified. Two of them were significantly associated with memory, attention and working memory, and executive or visuospatial function, respectively (all ps ≤ 0.048). The component more closely associated with cognitive domains includes items related to spatial orientation changes.

Conclusion

The SCC‐Q has the potential to become a valuable method for clinical practice in identifying individuals at risk of developing cognitive deficits. Further analyses are needed to confirm its validity.
Assessing the Role of PLCG2*M28L Risk In A Novel Mouse Model Late‐Onset Alzheimer’s Disease
Authors: Territo Paul R , Oblak Adrian L , Persohn Scott C , Bedwell Amanda A , Eldridge Kierra , Kotredes Kevin P , Pandey Ravi S , Rizzo Stacey J Sukoff , Carter Gregory W , Sasner Michael , Howell Gareth R , Lamb Bruce T
Published: December 2023

Background

MODEL‐AD has developed and characterized novel mouse models that aim to better phenocopy human LOAD for preclinical testing. More than 40 different models carrying combinations of LOAD risk factors have been created and assessed for relevance to LOAD. In this study, we aim to determine the mechanisms by which variations in the phospholipase C gamma 2 (PLCG2) gene increase risk for LOAD.

Methods

The M28L variant in PLCG2 (PLCG2*M28L) was prioritized as a LOAD risk factor. Mice were generated by CRISPR/CAS9 introduction of Plcg2*M28L variant on to LOAD1 (B6.APOE4.Trem2*R47H) and transcriptional profiling of brain hemispheres from 12 months old mice was used to evaluate molecular effects of Plcg2*M28L. To evaluate the contribution of Plcg2*M28L to LOAD risk, mice where placed on control or high fat diet (HFD) to serve as an environmental driver of neuroinflammation. Female and male LOAD1.Plcg2*M28L and LOAD1 control mice are being characterized at 4 and 12 mos through the MODEL‐AD phenotyping pipeline, which includes in vivo imaging of brain perfusion and glycolytic metabolism, multi‐omics, fluid biomarkers, cognition, and neuropathology.

Results

LOAD1.Plcg2*M28L mice showed brain transcriptomic alignment at 12 mos to human LOAD, and was prioritized for deep phenotyping. LOAD1 mice on HFD showed significant regional reductions in brain glycolysis and increased perfusion relative to controls yielding an uncoupled phenotype. By contrast, LOAD1.Plcg2*M28L mice showed a little to no regional changes in brain glycolysis or perfusion and few uncoupled regions. Multi‐resolution connectomics revealed a decrease in cluster number and organization in LOAD1 but not LOAD1.Plcg2*M28L for both sexes fed HFD compared with control diets. By 12 mos, male and female LOAD1.Plcg2*M28L mice on HFD showed opposite changes in clustering coefficient, network degree, and network density, with males showing a decrease and females an increase relative to controls. Mice carrying Plcg2*M28L variants are also being phenotyping at 18 and 24 mos.

Conclusions

Data collected to date reveal Plcg2*M28L on a LOAD1 background showed fewer sex‐dependent change in metabolism, perfusion and uncoupling on HFD when compared to LOAD1. These data suggest that the Plcg2*M28L risk variant on the LOAD1 background may result in an attenuated TREM2 signaling.
Accelerated cerebral amyloid angiopathy and vascular alterations in a mixed mouse model of Alzheimer’s disease and cerebral small vessel disease
Authors: Choi Sang‐Ho , Letica Leila , Brinson Lovisa Ljungqvist , Park Jung Eun , Silva Afonso C
Published: December 2023

Background

While aging is the primary risk factor for Alzheimer’s disease (AD), emerging evidence suggests that vascular dysfunction, present in cerebral small vessel diseases (CSVD) such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is also a major contributor for disease progression. Indeed, several studies have provided clinical evidence for a close synergistic relationship between AD and CSVD in cases where both diseases coexist. CSVD can elicit amyloid pathology, while Alzheimer’s‐associated cerebral amyloid angiopathy (CAA) and Ab plaque deposition may lead to concomitant vascular damage. Mutations in genes such as APP, PSEN1, and PSEN2 are not limited to AD, as APP mutations can also cause CAA, while PSEN1 and PSEN2 are involved in Notch3 signaling, a process known to be dysregulated in CADASIL. Here, we aimed to investigate the additive or synergistic effects of amyloid pathology and CADASIL‐related vascular damage on disease progression.

Method

To explore alterations in amyloid and vascular pathology when AD and CADASIL‐related CSVD coexist, we used PET/CT and histology to analyze over time the amyloid deposition in the form of plaques and CAA in a relevant mouse model of AD (5xFAD) carrying the Notch3 C456R mutation that causes CADASIL. Methoxy‐X04, Thioflavin‐S, or 6E10 were used to visualize amyloid accumulation in fixed brain tissues. The progression of microvascular dysfunction and neuroinflammation were assessed by immunofluorescence staining, Western blotting, RNA sequencing, and real‐time PCR.

Result

Adult 5xFAD‐Notch3C456R mice showed accelerated parenchymal and vascular amyloid deposition compared to 5xFAD mice. Progressive gliosis and microvascular damage were concomitant to parenchymal and vascular amyloid accumulation. These changes were associated with blood‐brain barrier disruption and reduction in pericyte coverage of cerebral capillaries.

Conclusion

We found accelerated amyloid plaque deposition, CAA, gliosis, and vascular damage in a mixed murine model of AD and CADASIL, suggesting that CSVD‐associated vascular changes directly contribute to AD pathology. This model offers novel opportunities to investigate the intricate interplay between CSVD and AD. This research was funded by NIH/NINDS grant RF1NS117486.
Oligomeric tau enters brain vascular endothelial cells and induces cellular senescence and brain microvascular dysfunction in tauopathy
Authors: Hussong Stacy A , Banh Andy Q , Van Skike Candice E , Dorigatti Angela O , Hernandez Stephen F , Hart Matthew J , Ferran Beatriz , Makhlouf Haneen , Gaczynska Maria , Osmulski Pawel , McAllen Salome , Dineley Kelly T , Ungvari Zoltan , Perez Viviana , Kayed Rakez , Galvan Veronica
Published: December 2023

Background

Vascular mechanisms of Alzheimer’s disease (AD) may constitute the most therapeutically addressable biological pathway underlying dementia. Soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, particularly in microvascular endothelial cells.

Methods

Primary human brain microvascular endothelial cells (HBEC) were exposed to tau oligomers. Microtubule stability, eNOS activation, and markers of senescence were measured. Mice expressing P301S‐mutant human tau (P301S(PS19) mice), a model of tauopathy, were given immunotherapy to selectively remove tau oligomers, or non‐specific IgGs. After measurements of vascular reactivity, eNOS activity and markers of senescence were measured in microvasculature purified from brain.

Result

Oligomeric tau significantly decreased microtubule stability and eNOS activity, and induced cellular senescence in primary HBECs. Microtubule destabilization, reduced eNOS activity, and increased markers of cellular senescence in brain microvasculature of P301S(PS19) mice were associated with impaired vascular reactivity, and the latter was negated by immunotherapy that specifically removed oligomeric tau from brain.

Conclusion

Brain microvascular deficits in P301S(PS19) mice modeling tauopathy, mediated by tau oligomers, may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of tau oligomers. Pathogenic tau oligomers and senescent brain microvascular endothelial cells may thus be targets for intervention in AD and other tauopathies.