bluuebunny/crossref_metadata_2025 huggingface dataset:
In silico prioritiziation of drug repositioning candidates for Alzheimer’s disease using signature search meta‐analysis
Authors: Bellur Orhan , Kastenmuller Gabi , Requena Francisco , Kaddurah‐Daouk Rima F. , Krumsiek Jan , Arnold Matthias
Published: December 2023

Background

Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with no effective treatment. Due to the genetic, pathological, and clinical heterogeneity among patients with AD, traditional drug development has struggled to target AD‐related pathways. Drug repositioning is a promising alternative to de novo drug development that investigates the potential of existing drugs to be effective in AD. Transcriptome signature matching is one repositioning approach that relies on the signature reversion principle to identify candidate drugs. In this study, we report on several potential candidate drugs for AD obtained by meta‐analyzing transcriptome‐based signature search methods on AMP‐AD nominated target genes for AD that are differentially expressed across seven brain regions.

Method

As search input, we used genes that are nominated as AD targets by the AMP‐AD initiative and significantly differentially expressed in at least one brain region. We compared their expression signatures against the CMAP and LINCS reference databases via four signature search methods (CMAP, LINCS, gCMAP, and correlation‐based methods). Significant candidate drugs were ranked based on their score for each search method and then meta‐analyzed using an ensemble rank aggregation approach employing a modified version of the Dowdall rule. Top‐scoring candidate drugs for AD were annotated using literature search and functional enrichment analysis results.

Result

Highest‐scoring drugs in the meta‐analysis included psycholeptics and psychoanaleptics (including acetylcholinesterase inhibitors), antibiotics, antivirals, histone deacetylase (HDAC) inhibitors, and anti‐inflammatory agents. Among those were drugs that are already used for symptomatic treatment of AD or are currently investigated in clinical trials. Novel candidate drugs reported here include antipsychotics, corticosteroids, and calcium channel blockers. Functional enrichment analysis of known targets of these candidate drugs showed shared targeting of biological processes related to dopaminergic synaptic transmission, calcium ion transport regulation, and alkaloid metabolic process

Conclusion

Gene expression signature matching is a promising approach for in silico drug repositioning. Our results describe several novel potential candidate drugs for AD obtained through the signature reversion principle, demonstrating the utility of meta‐analyzing data across brain regions and signature search strategies in prioritizing drug repositioning candidates for AD.
Biochemical Evidence for a Pathological Variant of Progressive Supranuclear Palsy
Authors: DeTure Michael , Chalk Jessica L , Murray Melissa E. , Dickson Dennis W.
Published: December 2023

Background

Tau proteins aggregate into spatially and morphologically distinct lesions in primary and secondary tauopathies. These signature lesions result from deposition of tau proteins that are distinctly modified via missense mutation and/or post‐translational modification for each disease strain. Identifying the unique tau protein abnormalities that lead to specific neurodegenerative diseases is beneficial in their early diagnosis and treatment. This is especially true for Progressive Supranuclear Palsy a primary tauopathy with clinical symptoms mirroring Parkinsonian syndromes and frontotemporal dementias.

Method

Biochemical analysis of tau aggregates from patients with a pathological diagnosis of Progressive Supranuclear Palsy (n = 60) demonstrate that the tau protein modifications observed in this disease result from tau that is specifically modified and thereby forms the basis of the distinct disease strains observed. Here data collected using the sarkosyl‐insoluble tau fractions from tissue samples of pathologically diagnosed patients with Progressive Supranuclear Palsy without comorbidities allows for the direct observation of the modifications. Most interesting is the variability of the tau proteins that actually accumulate for this disease opening up the possibility that tau strains may exist within any given tauopathy even as the clinical manifestations appear similar. This indicates that early and specific identification and detection of these strains is critical for the development of therapies for these diseases.

Result

Extraction and examination of sarkosyl‐insoluble tau proteins from deceased patients pathologically diagnosed with Progressive Supranuclear Palsy indicate that multiple tau strains exist within this primary tauopathy. Western blotting of these extracts from patient tissues demonstrates a unique banding pattern of insoluble tau in a subset of the cases that exhibit extreme hyperphosphorylation as indicated by additional high molecular weight tau banding. These patients also had an earlier age of onset and age of death indicating a more aggressive disease strain. Additional data is presented comparing the structure and seeding capability of this insoluble tau and the distribution and burden of insoluble tau in these Progressive Supranuclear Palsy patients compared to those with typical onset and insoluble tau signature.

Conclusion

Multiple pathological tau strains exist in Progressive Supranuclear Palsy.
Cognitive functions as predictors of daily functioning among older adults
Authors: Wardana Nido Dipo , Zhang Zhenyu , Lejko Nena , Opmeer Esther , De Deyn Peter Paul , Reesink Fransje E , Spikman Jacoba M , Herrmann Christoph S , Enriquez‐Geppert Stefanie , Aleman André , Ćurčić‐Blake Branislava
Published: December 2023

Background

Cognitive and daily functioning are conceptually critical in distinguishing Mild Cognitive Impairments (MCI) from dementia (Petersen, 2004), but findings on the association between the two have not always been consistent (e.g., Putcha & Tremont, 2016; Teng et al., 2010). We aimed to investigate whether cognitive functions could predict daily functioning among older adults.

Method

A total of 182 participants were included in this study, aged between 51 and 92 years. Cognitive functioning was measured using various neuropsychological tests which target different domains (e.g., trail‐making test, WAIS digit span, verbal fluency), while daily functioning was measured using the Functional Activity Questionnaire (FAQ) and the Instrumental Activities of Daily Living (IADL). The Geriatric Depression Scale (DGS) was used to assess depression as a possible moderator. The association between cognitive domains and daily functioning was examined using Partial Least Squares Structural Equation Modelling in R with the “seminr” package.

Result

A model with three cognitive predictors and no moderator provided the best fit to the data. However, the model only explained 16.7% of the total variance. Furthermore, only memory was significantly linked to daily functioning (b = ‐0.367, 95% CI [‐0.53 ‐0.18]), while language and attention/executive functions were not. Memory, language, and daily functioning showed good construct validity (all AVE > 0.5 and HTMT < 0.9), but “attention/executive function” construct suffered from poor convergent validity (AVE = 0.43) with only two out of its seven indicators demonstrating loading larger than 0.708. Also unexpectedly, depression was not found to be a significant predictor or a moderator.

Conclusion

Our preliminary results suggest that cognitive function explains a small portion of the daily functioning variance and memory was found to be the best cognitive predictor. Indeed, in addition to executive function, memory has been rather consistently mentioned as crucial in the maintenance of daily functioning (Pérès et al., 2008; Royall et al., 2007). The lack of evidence for the role of executive function in this study might be due to the poor convergence of the “attention/executive function” construct in our model, suggesting that it may represent different cognitive functions and should be investigated further.
Predicting Transitions from Mild Cognitive Impairment to Dementia within 5‐years
Authors: Amini Samad , Hao Boran , Yang Jingmei , Karjadi Cody , Kolachalama Vijaya B. , Au Rhoda , Paschalidis Ioannis
Published: December 2023

Background

Early detection of individuals at high risk of future progression toward dementia is in great need, particularly in the era of emerging treatments for Alzheimer’s disease. Given the easier administration of neuropsychological (NP) tests over invasive and expensive biomarker acquisition, we seek to predict the future cognitive status of an individual based on digital voice recordings of NP exams.

Method

We utilized automatic speech recognition and natural language processing techniques to create an automated tool that predicts if an individual with mild cognitive impairment (MCI) will develop dementia in a fixed follow‐up window (5 years). We characterize the predictive accuracy of this approach using data from the Framingham Heart Study. First, the automated transcription of the digital voice recordings were classified into 8 main NP sub‐tests including memory assessment, naming and language skill, verbal fluency, general questions, etc. Using a large language model, only the participants’ sentences were encoded into quantitative data. These data and the participants’ characteristics, such as age, sex, ApoE4 (+/‐) genotype, and education were employed to train and test a binary classifier, predicting dementia withing 5 years after a positive MCI diagnosis. We also provide a comparison between our approach and alternative models using demographics and ApoE genotype or the Mini‐Mental State Examination (MMSE) score.

Result

We evaluated the performance of the classification task on the data containing 111 stable MCI and 103 progressive MCI subjects. Our method achieved an average accuracy of 75.5% on the held‐out test data while a baseline model using age, sex, education, and ApoE has an average accuracy of 71.8%. The sensitivity and specificity of the proposed method versus the baseline model are 78.2% vs. 81.8% and 72.7% vs. 61.8%, respectively. Our approach also significantly outperforms the model based on the MMSE score by a margin of 14% in accuracy.

Conclusion

We have analyzed digital voice recordings of NP exams for participants with MCI to predict their cognitive status in 5 years. The proposed approach offers a fully automated procedure with higher accuracy, providing an opportunity to develop an accessible and easy‐to‐administer screening tool that could be easily adapted to any language.
Leveraging systems biology approaches and single‐nucleus RNA‐seq to study sex differences in AD
Authors: Brase Logan , Dunn Amy R , Morris John C , Perrin Richard J. , Dumitrescu Logan , Kaczorowski Catherine C. , Hohman Timothy J. , Karch Celeste M. , Harari Oscar , Benitez Bruno A.
Published: December 2023

Background

There is increasing evidence indicating sex‐specific patterns in disease manifestation and sex differences in the rates of cognitive decline and brain atrophy. Sex‐related differences in AD‐associated genes are starting to emerge, but these have not been systematically studied at cell‐type‐specific transcriptome‐wide expression levels. We leveraged single‐nucleus RNA‐seq (snRNA‐seq) and systems biology approaches to identify transcriptomic modules in human brains and determine the modules associated with sex‐AD interactions.

Methods

We studied snRNA‐seq data from the parietal cortex of 67 pathologically confirmed controls, sporadic AD (sAD), autosomal dominant AD (ADAD), and other neurodegenerative samples from the Knight ADRC and DIAN cohorts1, and used Celda2 to co‐cluster cells and genes into subpopulations and modules. This approach identified clusters that correspond to previously described cell types1. We used linear mixed models to identify those modules associated with a sex‐AD interaction. For each nominally significant (P<0.05) module, we isolated the top genes that accounted for 80% of the module expression signature and tested each for a sex‐AD interaction.

Results

When run on 38,584 astrocytes, Celda split 13,302 genes into 65 gene modules. Module L17 was nominally significant (P = 0.04), with 55 out of 194 genes accounting for ∼80% of the module signature. After multiple testing correction, two genes, ENTREP1/FAM189A2 (Adj.P = 1.57´10−2) and CD38 (Adj.P = 1.80´10−2), showed a significant sex‐sAD interaction in expression (Figure 1, Table 1). ENTREP1 facilitates the removal of the chemokine receptor CXCR4 from the plasma membrane reducing the downstream effects of CXCL12/CXCR4 signaling3 including astrocytic inflammation response4 and release of glutamate as a gliotransmitter5. Studies have linked ENTREP16 and CXCL12/CXCR47 to neurodegeneration. CD38 expression is influenced by cytokine and chemokines released by senescent cells, which increase with age, AD, and other neurodegenerative diseases8. Increased expression of CD38 increases proinflammatory cytokine release and reduces NAD‐dependent enzyme activity, increasing DNA mutations, mitochondrial dysfunction, and oxidative stress. Knockouts of CD38 in mouse showed significant decreases in Aβ plaque load and soluble Aβ levels9.

Conclusion

These results suggest that the known neurodegenerative genes ENTREP1 and CD38 are uniquely modulated by biological sex in relation to AD within astrocytes potentially contributing to the clinical differences seen between males and females.
The association of blood‐based biomarkers of neuropathology with cognitive performance and dementia in a diverse, population‐based sample of US adults
Authors: Faul Jessica D , Crimmins Eileen M. , Thyagarajan Bharat , Kim Jung Ki , King Jonathan W , Weir David R , Langa Kenneth M
Published: December 2023

Background

The association of blood‐based biomarkers of neuropathology with cognition and dementia, including potential variation by race/ethnicity (whites, blacks and Hispanics), has not been examined in large, diverse, population‐based samples of adults.

Method

The sample included Health and Retirement Study (HRS) respondents over age 50 with blood‐based neuropathology biomarker, demographic, and cognitive data (n = 4,214). A𝛃‐40, A𝛃‐42, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured in plasma (Quanterix Neurology 4‐Plex E kit), and phosphorylated tau (pTau‐181) was measured in serum (Quanterix Advantage V2.0 kit). Cognitive tests included immediate and delayed word recall, serial 7s, and backward counting (total score 0‐27). Dementia classification relied on a diagnostic algorithm previously validated in HRS. Linear and unconditional logistic regressions were weighted to account for sample design and used to model associations between the biomarkers and the cognitive score/dementia classification after controlling for age, sex, and batch effects.

Result

About 80% of the sample was white, 10% black, and 10% Hispanic. Correlations were modest among pTau‐181, NfL, and GFAP (r = 0.29‐0.46).

When the biomarkers were analyzed individually, higher A𝛃‐42/A𝛃‐40 ratio was associated with higher cognitive score among whites. Higher NfL was associated with lower cognitive score in the total sample and in each race/ethnic group (whites, blacks and Hispanics). Higher pTau‐181 was associated with lower cognitive score in the total and white sample. Higher GFAP was related to lower cognitive score in the total, white, and Hispanic samples. In a model that included all four biomarkers, GFAP remained significantly related to cognitive performance in the total sample, and NfL remained significantly related to cognitive performance in the total sample and in each race/ethnic group.

When the biomarkers were analyzed individually, higher NfL was associated with higher likelihood of dementia in the total sample. Higher pTau‐181 was associated with higher likelihood of dementia among whites. Higher GFAP was associated with dementia in the total and white samples, alone and in the fully adjusted model with all four biomarkers.

Conclusion

These results show the importance of examining blood‐based biomarkers of neuropathology as predictors of cognitive performance and dementia in diverse, population‐based samples.
The influence of vascular pathology on the generalizability of machine learning models for cognitive performance estimation
Authors: van Haaften Myrthe F , Yu Jing , Seelaar Harro , Vernooij Meike W , Bron Esther E
Published: December 2023

Background

Image‐based machine learning models are promising to aid diagnosis in dementia, e.g. by diagnostic classification or estimating cognitive performance. However, the contribution of vascular pathology is often ignored, although many patients have mixed pathologies. This may hamper model generalizability from research setting to clinical practice, as the models are generally developed on populations with lower vascular burden than is encountered clinically. This study aims to evaluate whether model generalizability is influenced by differences in vascular pathology load between training and test groups, represented by white matter hyperintensities (WMHs).

Method

We developed a convolutional neural network to estimate cognitive performance through ADAS13. We included 4791 timepoints from 1632 ADNI subjects. To mimic differences in vascular burden between research and clinical populations, we split the data into a low, middle and high WMH load group using WMH ratio tertiles (WMH volume corrected for intracranial volume). The model was applied to maps derived from T1‐weighted and FLAIR brain MRI using voxel‐based morphometry: model 1 (gray matter density map (GMDM), age, sex), model 2 (GMDM, WMH density map (WMHDM), age, sex) and model 3 (GMDM, log(WMH ratio), age, sex) (Fig. 1). First, we trained all models on the low WMH load group, meaning to test on the high WMH load group to assess generalizability. Second, we trained models 1 and 2 on all data. Mean Absolute Error (MAE) served as the performance metric.

Result

The models trained on the low WMH load group (MAE = 5.08 – 5.41) performed similar to constant value prediction (MAE = 5.63) (Fig. 2, circles). Using all data, models did train successfully (model 1: MAE = 5.64, model 2: MAE = 6.31, constant value: MAE = 7.39) (Fig. 2, crosses). Because of the suboptimal model training in the low WMH load group, especially for individuals with higher ADAS13 scores which were underrepresented in the data (Fig. 3), we could not evaluate generalizability to the high WMH load group.

Conclusion

This study was unable to provide new insight into the influence of vascular pathology on the generalizability of machine learning models in dementia. More clinically representative data is needed, covering the full cognitive performance spectrum and higher vascular pathology loads.
Assessment of apathy‐like behaviour in transgenic mouse models of neurodegenerative diseases
Authors: Robinson Lianne , Barraza Maria Cacho , Riedel Gernot
Published: December 2023

Background

Apathy is the most common behavioural and psychological symptom in neurodegenerative diseases like Alzheimer’s disease (AD), frontotemporal dementia (FTD) or Parkinson’s disease (PD). Apathy typically includes a loss of motivation, initiative and interest, listlessness and indifference, flattening of emotions, absence of drive and passion. Scientists have defined this as a reduction/lack in goal direct behaviour. There are currently no specific treatment options for apathy. In experimental models, selective symptoms of apathy‐like behaviour are measured in goal directed or nesting behavioural tasks, which report on their motivation to perform daily activities. A richer understanding of apathy, however, may be achieved through the development of a battery of tests including goal directed, nesting, anhedonia, activity monitoring, and social interaction. These have been applied here to several animal models of neurodegeneration.

Method

Male and female transgenic mice (aged 6 – 8 months) including tau over‐expressors L1 for AD and L66 for FTD (Melis et al. 2015); PLB4 BACE1 mouse model for AD (Plucinska et al. 2014); L62 alpha‐synuclein mouse model of PD (Frahm et al. 2018) and relevant wild type (WT) controls were utilised in this study. Animals were tested in a series of behavioural tests including the nest building task, sucrose preference test, buried cookie test, social interaction, and home cage activity. Performance was recorded and analysed by behavioural tracking software as indicators of apathy‐like behaviour.

Result

Two models showed reproducible results compared with previous studies. Intriguingly, L66 FTD mice presented with deficits in sucrose preference and nest‐building, but not a lowering of general activity. Although this was not found for the sister strain, L1 mice which has AD‐like pathology. Very much unexpected is the observation that neither the amyloid nor the synuclein‐based models showed any significant behavioural anomalies. Further detailed investigations are ongoing.

Conclusion

Initial observations have confirmed that the transgenic models for neurodegenerative diseases show different levels of apathy‐like behaviour. It appears that the phenotype in L66 is a tau‐related anomaly specific to the tau species expressed, i.e. the mutation at P301S. The lack of deficits in all other models warrants in‐depth confirmation and analysis.
Gene‐Based Analysis with Functional Annotation in 2680 South Asians from the LASI‐DAD Study
Authors: Abu‐Amara Hasan , Zhao Wei , Li Zheng , Dey Aparajit Ballav , Zhou Xiang , Lee Jinkook , Kardia Sharon L R , Smith Jennifer A
Published: December 2023

Background

The prevalence of dementia among South Asians across India is as high as 10% in those 55 years and older, yet little is known about the risk dementia factors in this population. To date, most known genetic risk loci of Alzheimer’s disease (AD) were identified from studies conducted in European Ancestry (EA) participants. The full mutational spectrum and the functional relevance of those loci in South Asians remains unknown. Analyzing DNA sequence data poses challenges due to the large number of rare variants tested, with most variants likely not associated with dementia. These challenges can be addressed with an annotation‐informed gene‐based analysis.

Method

Using whole‐genome sequence data from 2680 participants from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI‐DAD), we performed a gene‐based analysis of 84 genes known to be associated with AD in EA. We investigated associations with the Hindi Mental State Examination (HMSE) score, general cognitive function, and five cognitive domains. For each gene, we examined missense/loss‐of‐function (LoF) variants and brain‐specific promoter/enhancer variants, separately, both with and without incorporating additional annotation weights (e.g., deleteriousness, conservation scores) using the variant‐Set Test for Association using Annotation infoRmation (STAAR).

Result

In the missense/LoF analysis, when controlling for age, sex, state/territory, and the first 10 principal components, 16 genes were nominally associated with at least one cognitive outcome (p<0.05). Three genes (APOE, PICALM, TSPOAP1) were significant after multiple testing correction (FDR q<0.1). In the brain‐specific promoter/enhancer analysis, 21 genes were nominally significant, but none were significant at FDR q<0.1. Results remained similar after adding annotation weights. The most strongly associated variants in each gene were rs429358 (APOE), rs779406084 (PICALM), and rs9913145 (TSPOAP1). rs779406084 is a missense mutation that is more prevalent in this Indian sample (MAF = 0.075%) compared to EA (MAF = 0.0015%).

Conclusion

Some genes associated with AD in EA are also associated with cognitive outcomes in South Asians in India. Analyzing sequence data in South Asians provides opportunities to identify potential novel causal variants that are enriched in this population.
Non‐invasive Flicker Neurostimulation Boosts Resilience to Psychological Stress
Authors: Franklin Tina C , Goodson Matthew , Gajelli Tarini , Rutledge Catherine , Tharayil Jacob , Pennebaker Sarah , Naik Arya , Singer Annabelle C , Lab Singer
Published: December 2023

Background

Chronic stress promotes life‐long risk for neuropsychiatric decline by increasing neuroinflammation and disrupting synaptic health and plasticity. Our lab and others have recently demonstrated that non‐invasive gamma sensory flicker stimulation modulates inflammatory signaling, restores microglia function and improves cognitive performance in mice models of Alzheimer’s disease (AD). However, no research to date has studied the effects of flicker in the context of stress. Accordingly, our goal for this study was to determine how sensory flicker stimulation mitigates neuropsychiatric‐like behavioral deficits and rescue glia and synapse pathology following chronic stress.

Method

Daily flicker intervention was introduced concomitantly with daily stress exposure (28 days) at multiple frequencies in male and female C57BL6 and Thy1‐GFP mice (n = 6/group per sex). The mice were then tested for anxiety‐like and anhedonia using a range of behavioral tests. Next, we quantified spine density changes in Thy1‐GFP mice and quantified GFAP‐labeled astrocyte morphology change, a reliable proxy for astrocyte reactivity, in the medial PFC using the semi‐automated Imaris imaging software to determine synaptic health and inflammatory profile, respectively.

Result

We show for the first time that stress‐induced morphological changes in the medial PFC are modulated in a sex‐, and frequency‐specific manner that coincides with behavioral resilience in stressed mice. Our findings indicates that audio‐visual flicker protect against stress‐induced behavioral deficits (p<0.0001) and improves neuroinflammation (p<0.01) in a sex‐ and frequency‐specific manner.

Conclusion

Together, these findings show frequency tunable flicker intervention improves stress pathology and may prevent neuropsychiatric health decline in conditions with sex dimorphic symptoms and prevalence.
The Emory‐Sage‐SGC TREAT‐AD Center: Tool development for novel targets in Alzheimer’s Disease
Authors: Leal Karina , Axtman Alison D. , Betarbet Ranjita , Brennan Paul E , Carter Gregory W , Fu Haian , Greenwood Anna K , Longo Frank M. , Edwards Aled M , Levey Allan I. , Center The Emory‐Sage‐SGC TREAT‐AD
Published: December 2023

Background

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases affecting over 55 million people worldwide. Over the last 20 years, AD research has focused on a limited number of potential drug targets. Given the demonstrated heterogeneity of the disease in biological and genetic components, there is a need to evaluate a broad range of therapeutic hypotheses for target prioritization and development. The Emory‐Sage‐SGC TREAT‐AD Center is generating and openly distributing validated experimental tools necessary to test target predictions generated through sequence‐based characterization of human disease state. We believe that these tools and reagents, including chemical and biological probes that target the multifaceted dysregulation in the brains of AD patients will advance the discovery of potential drug targets for AD.

Method

Our Center uses integrated computational approaches to identify target predictions from a set of prioritized therapeutic hypotheses. The current target portfolio was assembled by evaluating prioritized understudied proteins by the Accelerating Medicines Partnership in AD (AMP‐AD) consortium and additional NIA‐supported AD consortia. Nominated targets were evaluated by calculating an unbiased target risk score, literature score, and druggability. Targets are then mapped to 16 biological domains (BDs) that describe and codify the different processes that are dysregulated in AD and prioritized based on multiple lines of evidence for overall AD‐risk. Targets that meet criteria for development are evaluated to identify a set of experimental reagents necessary for hypothesis testing, termed a “target enablement package (TEP).

Result

We have prioritized more than 30 understudied targets for TEP development. For each understudied target, a TEP includes expression constructs, purified protein and methods, validated knockout cell lines, and antibody validation. All reagents are developed to meet established quality criteria. For a subset of tractable targets additional TEP components include assay development, crystal structures, screening, and probe development. Advanced targets include SYK, DDX1, SFRP1, SDC4, ARHGEF2, and CAPN2. TREAT‐AD investigators place all data, knowledge, reagents, and tools into the open domain with no intellectual property claims.

Conclusion

All data, protocols, reagent sets, and chemical tools will be made widely available on the AD Knowledge Portal. For more information see www.treatad.org.
Microglial phenotype and proinflammatory gene induction in human prefrontal cortex in Alcohol Use Disorder overlap with Alzheimer’s Disease
Authors: Crews Fulton Timm
Published: December 2023

Background

Alcohol Use Disorder (AUD) and heavy alcohol abuse are associated with dementia. However, studies focused on Alzheimer’s disease (AD) tend to exclude heavy alcohol drinking patients. We hypothesize microglial phenotype changes in AUD contribute to degeneration that parallels AD.

Method

Orbital frontal cortex (OFC) from moderate drinking controls and heavy drinking AUD individuals paired by age were obtained from the New South Wales Tissue Resource Center in Sydney Australia. Tissue blocks were used for RTPCR gene mRNA and paraffin sections for immunohistochemistry assessment of microglial and proinflammatory genes and proteins, respectively. Fluoro‐Jade B, TUNEL stain and neuron marker NeuN were used to assess degeneration.

Result

AUD OFC expressed increased levels of proinflammatory HMGB1, RAGE, and multiple Toll‐like receptors (TLR). In addition, AUD OFC increased expression of the TLR adaptor protein myeloid differentiation primary response 88 (MyD88), NFκB, and proinflammatory cytokines, chemokines, and their corresponding receptors. Iba1, a marker of monocytes and microglia, is increased in AUD, but not mRNA levels. Macrophage‐1 antigen, a complement receptor, is increased in AUD cortex as is CX3C chemokine receptor 1 (CX3CR1), the fractalkine receptor. OX42 staining (CD11b) in also increased. Microglial markers P2ry12, and CSF1R also show greater cellular staining in human AUD. The lysosomal scavenger receptor marker CD68 is also increased in AUD cortex. CX3CR1 and CD11b mRNA are increased in AUD cortex, but not CD68. Interestingly, TMEM119, a specific microglial marker, is decreased in AUD, both mRNA and protein staining in contrast to other markers increasing. Assessment of DNA oxidation using 8‐hydroxy‐2'‐deoxyguanosine (8‐OHdG) a biomarker of oxidative DNA/RNA damage 8‐OHdG+IR indicated AUD more than doubled cortical cells with this marker. Induction of HMGB1‐TLR‐MyD88‐NFκB proinflammatory signaling pathways, oxidative stress and microglial activation correlate with markers of neurodegeneration.

Conclusion

The increased expression of TLR receptors, MyD88 and NFkB and increased proinflammatory cytokines are consistent with increased microglial activation and oxidative stress induced degeneration. Studies support alcohol activated microglia‐monocytes as driving loss of NeuN and other neurodegeneration markers. The reduced TMEM119 level with other markers increasing may indicate monocytes are replacing microglia in AUD cortex.
Exploring Predictable CSF derived biomarkers between mutation carriers and noncarriers in autosomal dominant Alzheimer’s disease
Authors: Shen Yuanyuan , Morris John C , Llibre‐Guerra Jorge J , Karch Celeste M. , Xiong Chengjie , Perrin Richard J. , Renton Alan E. , McDade Eric , Bateman Randall J. ,   Dominantly Inherited Alzheimer Network (DIAN), Cruchaga Carlos
Published: December 2023

Background

Autosomal dominant Alzheimer’s disease (ADAD) is caused by known genetic mutations that start a cascade of events leading to Aβ deposition, tau pathology and neurodegeneration. Mutation carriers (MCs) are characterized by substantial amyloid accumulation, and dementia onset at or around the age of parental dementia onset. CSF, plasma Aβ, tau and ptau are well known biochemical biomarkers for AD. However, other proteomic changes associated with ADAD have not been explored in a systematic manner. Here, we generated high‐throughput CSF proteomic data from MCs and noncarriers (NCs), and identified proteins associated with mutation status and estimated years to symptom onset (EYO), in Dominantly Inherited Alzheimer Network (DIAN).

Method

A total of 7,011 CSF proteins measured with the SomaScan 7k platform passed QC and Lumipulse assays from in 476 DIAN participants: 281 MCs, 185 NCs. We utilized linear models with participants’ status, age, gender and surrogate variables to identify proteins associated with mutation status. Then, predictable trajectory intersection of EYO between MCs and NCs were identified. We applied enrichment analysis to evaluate biological functions of significant proteins.

Result

We identified 243 significant proteins (FDR < 0.05) associated with status. The ‘Established’ AD biomarkers, phospho‐Tau181, Tau, neurofilament light polypeptide, Aβ42 were our top 5, 19, 25and 33 hits. The top 10 proteins included SMOC1, 14‐3‐3 proteins, SLIT2 or DNAJB9. Through the EYO trajectory intersection, we found several proteins with trajectory changes earlier than Aβ (‐11.0 years) or NEFL (‐11.6 years); these include SMOC1 and 14‐3‐3 proteins, with changes ‐30.7 and ‐13.5 years before the estimated symptomatic onset. Gene ontology analysis suggested that the identified proteins were enriched in axon development, axonogenesis and neuron projection morphogenesis. Alzheimer disease and pathways of neurodegeneration were identified by KEGG pathway gene set enrichment. The identified proteins were enriched in astrocytes, macrophages and neurons by cell marker analysis.

Conclusion

Our analyses identified 243 proteins associated with ADAD mutation status. Of these 93% of them change before the estimated symptomatic onset and could be leveraged to better predict the year of symptom onset. The enrichment analysis revealed the identified proteins may closely associated with the development of Alzheimer disease.
Effect of photobiological modulation therapy on cognitive impairment and cardiovascular structure in an APP/PS1 mouse model of Alzheimer’s Disease
Authors: Haghkar Mahdi , McDevitt Ross A , Zernetkina Valentina I , Grigorova Yulia N , Wei Wen , Syed Sunayana Begum , Fox Shanaya , Santos Carla Rocha Dos , Juhasz Ondrej , Morrell Christopher H , Lakatta Edward G , Fedorova Olga V
Published: December 2023

Background

Photobiological modulation (PBM) therapy, a form of low‐dose light therapy, is beneficial in treating various disease conditions including Alzheimer’s disease (AD). Double‐transgenic mice (APPswe/PS1dE9) develop progressive accumulation of amyloid‐β (Aβ) plaques, cognitive impairment, and alterations in cardiovascular structure and function, and represent a model of AD. Prior studies have shown that PBM therapy reduces the size and number of Aβ plaques in the neocortex and hippocampus in the mouse models of AD. The aim of this study was to investigate the effects of PBM on cardiovascular structure and function and cognitive function in the aged AD mice.

Methods

Six‐month old female AD (APPswe/PS1dE9; AD‐PBM, n = 8) and wild type mice (WT‐PBM, n = 8) were exposed to near‐infrared light (wavelength 850 nm, 4.5 J/cm2, 3min/day, 5 days/week) for 6 months. Control mice (AD‐CNT, n = 6; WT‐CNT, n = 6) were placed under the PBM apparatus without turning the light on for 3min/day, 5 days/week. Cardiac parameters were measured by echocardiography. Gait analysis (DigiGait), home cage activity (HCA), and spatial working memory (indicated by alternation rate in cross maze test, CM) were assessed after 6 months of treatment. Group differences were identified by two‐way ANOVA.

Results

In HCA test, the AD‐CNT mice exhibited circadian locomotor hyperactivity at night‐time relative to WT‐CNT mice (Figure 1A, B), which was reduced by PBM. AD‐CNT mice had lower alternation rates in CM, indicating spatial working memory impairment. PBM had minimal effect on this parameter (Table 1). The AD‐CNT vs. WT‐CNT mice manifested differences in several gait parameters, specifically, they demonstrated a lower fore propel time than WT‐CNT. PBM normalized this parameter in AD‐PBM mice to the level of WT‐CNT (Figure 1C). Both WT‐PBM and AD‐PBM mice had improved cardiovascular structure, which was demonstrated by lower relative wall thickness of left ventricle (LV) and LV mass, and higher LV volume at the end of diastole in PBM‐treated vs. correspondent CNT groups (Table 1, Figure 2).

Conclusion

PBM improved cardiovascular structure and AD‐associated cognitive impairment in the APP/PS1 mouse model. It is possible that more effective cardiovascular structure and function contributes to Aβ removal from the brain after PBM treatment.

Supported by NIA/NIH/IRP
Blood‐based Biomarkers, Kidney Disease, and Albuminuria in the Systolic Blood Pressure Intervention Trial (SPRINT)
Authors: Gaussoin Sarah A. , Pajewski Nicholas M. , Reboussin David M. , Williamson Jeff D.
Published: December 2023

Background

There is significant current interest in the use of non‐invasive blood biomarkers to characterize risk for, and progression to, Alzheimer’s’ disease (AD) and related dementias. Population‐based cohorts have examined the relationship between protein markers of AD and neurodegeneration, showing consistent associations with the presence of comorbidity, and in particular, chronic kidney disease (CKD). However, these studies have had limited racial diversity, and have not examined relationships with urinary albumin excretion.

Method

We assayed amyloid beta 40 (Aβ40), Aβ42, total tau, and neurofilament light chain (NfL) in stored blood samples from 508 participants (≥60 years) in SPRINT. We computed the ratio of Aβ42/Aβ40, and converted all measures to standardized Z‐scores in order to compare estimates. Using linear models, we examined the association of chronic kidney disease (CKD) with the blood measures, defined as a baseline estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2. We also considered several additional analyses, including utilizing eGFR based on Cystatin‐C versus serum creatinine, as well as examining the relationship of albuminuria and race/ethnicity with the blood measures in participants without CKD at trial baseline.

Result

Participants (42.7% female, 31.9% non‐white) with a mean age of 69.9 years. There was a significant association between CKD and total tau, Nfl (p<0.001), but not with Aβ42/Aβ40 (p = 0.09). Participants with CKD exhibited higher levels of both total tau (least squares (LS) mean = 0.27, 95% CI: 0.12, 0.43) and NfL (LS mean = 0.67, 95% CI: 0.52, 0.83). Relationships were similar for eGFR based on cystatin C versus serum creatinine. After excluding participants with CKD (N = 352, 39.8% female, 34.1% non‐white, mean age of 68.8), there were not significant relationships between albuminuria with any of the biomarkers (p>0.05), nor was there a significant association between race/ethnicity and total tau, NfL, or Aβ42/Aβ40 (p>0.05).

Conclusion

In a racially diverse subgroup of SPRINT participants, there were significant relationships between kidney function, defined via eGFR, with total tau and NfL, but not for the ratio of Aβ42/Aβ40. We did not observe any association between albuminuria and these blood measures of Alzheimer’s disease and non‐disease‐specific neurodegeneration.
Exploring the Potential of Fenamate NSAID Analogs for the Treatment of Alzheimer’s Disease
Authors: Shalaby Karim , Nguyen‐Tran Van , de la Fuente Alberto , Thompson Ian , Abdesselem Houari , Ouararhni Khalid , Karim Nasser
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common form of dementia, and its prevalence continues to increase with absence of available interventions. Drug repurposing accelerates the drug discovery process as therapeutics with known safety and toxicology profiles are considered. Although the blood‐brain barrier (BBB) prevents uptake of most pharmaceuticals, our laboratory previously showed that tolfenamic acid (TA), a fenamate non‐steroidal anti‐inflammatory drug (NSAID) with known anti‐cancer effects, can cross the BBB and slow the progression of AD (Zawia et al, 2018).

Method

In the present study, we test 2‐(2‐Cyanophenylthio) benzoic acid (CBA) and Niflumic acid (NA), small molecule analogs of TA that showed better safety and efficacy at targeting neurodegenerative pathways in vitro, and a similar mechanism of action to TA. We aimed to examine the effects of the analogs on in mice using proteomic and transcriptomic analyses.

Single dose study of TA, CBA, and NA was carried out in C57BL/6 mice following oral administration at 100 mg/kg. Differential expression of genes and proteomic biomarkers in mice cortices were analyzed between each treatment group and a corresponding control group.

Results

Analysis of the number of perturbed genes revealed that the drugs demonstrate limited off‐target effects. Bioinformatic analyses revealed that the therapeutics targeted cancer and neurodegenerative pathways including autophagy, inflammation, and neuronal trafficking. CBA and NA shared common downstream targets and pathways suggesting that they may have a similar mode of action.

Conclusion

We found a set of differentially expressed genes that have been linked to processes involved in AD pathogenesis such as the production and clearance of neurotoxic Aβ peptides, tau phosphorylation, regulation of oxidative stress, and inflammatory processes. These results suggest that the drugs may influence pathways related to the pathogenesis of AD and support the potential of drug repurposing of fenamate NSAIDs such as TA, and its analogs CBA and NA, as a strategy for cancer and neurodegenerative disease therapy. Further research is needed to confirm the effect of the analogs on AD biomarkers and their efficacy as therapeutics for AD.
Redefinition of dementia care in Italy in the era of anti‐amyloid agents for Alzheimer’s disease: an Expert Opinion and practical guideline
Authors: Filippi Massimo , Cecchetti Giordano , Cagnin Annachiara , Marra Camillo , Nobili Flavio , Parnetti Lucilla , Agosta Federica
Published: December 2023

Background

Current evidence from clinical trials testing anti‐beta amyloid (Aβ) monoclonal antibodies (mAbs) in patients with early Alzheimer’s disease (AD) suggests a likely authorization in Europe in the next years, requiring a huge change of dementia care in all countries.

Method

A group of prominent AD clinical experts in Italy met to discuss patients’ selection for immunotherapies and management strategies. The current diagnostic‐therapeutical standards in Italy were taken as the starting‐point.

Result

Immunotherapies’ prescription must follow a biological diagnosis of AD, defined through the assessment of both amyloidopathy and tauopathy biomarkers. Their high risk/benefit ratio, moreover, needs a highly specialized diagnostic assessment, which should be dispensed by a neurologist. The Expert Panel suggests a reorganization of dementia and cognitive decline centers (CDCD) for the diagnosis of AD in Italy into 3 levels of increasing complexity, with specific tasks and requirements/resources: 1) community centers, with at least 1 neurologist / geriatrician / psychiatrist, with global screening purposes; 2) first‐level centers, deputed to biological diagnosis; and 3) second‐level centers, requiring the presence of on‐site facilities for the biological diagnosis and of at least one neurologist with expertise also in rarer neurodegenerative syndromes. Finally, specific characteristics of a center deputed to prescribe anti‐Aβ mAbs were discussed, highlighting the need for clinical and neuroradiological management protocols.

Conclusion

The number of potentially treatable patients in Italy will be tens of thousands. To successfully face such a breakthrough, a quick reorganization of Italian CDCDs will be required, together with the allocation of the necessary resources.

Funding: Unrestricted grants from Biogen.
A 10‐minute Digitally Administered and Scored Neuropsychological Protocol Assessing Executive Control and Episodic Memory
Authors: Libon David J , Swenson Rodney , Jannati Ali , Bates David , Tobyne Sean , Pascual‐Leone Alvaro , Gomes‐Osman Joyce Rios
Published: December 2023

Background

Digital assessment technology provides rapid and reliable assessment of neurocognitive abilities associated with Alzheimer’s Disease and Related Dementia (ADRD) and Mild Cognitive Impairment (MCI). Dysexecutive and amnestic impairment typify many ADRD and MCI disorders. Here, we evaluate a 10‐minute digitally administered protocol assessing these neurocognitive constructs.

Method

229 community dwelling participants were assessed (age = 68.32+9.85; education = 15.01+2.58, MMSE = 26.84+2.78; 144 females). Executive abilities were assessed with three trials of 5‐digits backward digit span test (BDST) and the ‘animal’ fluency test. Episodic memory was assessed with a 6‐word Philadelphia (repeatable) Verbal Learning Test (PrVLT) consisting of 2 immediate free recall (IFR) trials, delayed free recall (DFR), and delayed recognition. Traditional pencil and paper testing was not used. Data were obtained with an iPad processed using automatic speech recognition.

Result

A K‐means cluster analysis (k = 3) classified participants with possible dementia (pDem = 31), MCI (n = 96), and cognitively normal (CN, n = 100; Table 1). Groups differed from each other on all three P(r)VLT parameters (p = 0.001). CN participants outperformed other groups on executive measures (p = 0.001). All between‐group analyses yielded large effect sizes (η2 = 0.277–0.642). Logistic regression analysis using P(r)VLT‐DFR, P(r)VLT‐recognition, BDST, and ‘animal’ fluency parameters classify MCI and pDem participants into their respective groups compared to CN participants (p = 0.003). For the pDem group, within‐group t‐tests found rapid forgetting (PrVLT‐DFT<PrVLT‐IFR trial 2, p = 0.013; PrVLT‐recognition<PrVLT‐DFR (p = 0.013). Additional, within‐group pDem group comparisons found no differences between P(r)VLT‐recognition and either executive tests. Within group comparisons for the MCI group found P(r)VLT delayed recognition improved compared to P(r)VLT delayed free recall (p<0.001), and worse performance on both executive measures compared to P(r)VLT‐ recognition (p = .001). All of these comparisons are consistent with a mild dysexecutive syndrome.

Conclusion

The protocol described above is efficient, reliable, removes any inter‐rater reliability issues, and is able to operationally‐define dysexecutive and amnestic cognitive impairment ‐ key neurocognitive constructs related to ADRD and MCI. This 10‐minute digitally administered and automatically scored neuropsychological protocol assessing executive abilities and episodic memory could easily be deployed in clinical trials and in primary‐ and specialty‐care settings to screen for emergent cases of MCI and ADRD by efficient assessment of episodic memory and executive abilities.