bluuebunny/crossref_metadata_2025 huggingface dataset:
House dust mite‐induced asthma exacerbates Alzheimer's disease by increasing amyloid beta accumulation and neuroinflammation
Authors: Sahu Bijayani , Nookala Suba , Floden Angela M , Combs Colin K
Published: December 2022

Background

Alzheimer's disease (AD) is an age‐related neurodegenerative disorder affecting around 35 million individuals worldwide. Besides aging, various comorbid factors increase the risk of AD, including air pollution and asthma. Epidemiological studies have reported a 2.17‐fold higher risk of dementia in asthmatic patients. However, the molecular mechanism(s) underlying this asthma‐associated AD exacerbation is unknown. This study was designed to explore house dust mite‐induced asthma effects on AD‐related brain changes using the App
NL‐G‐F transgenic mouse model.

Method

Male and female C57BL/6 wild type and AppNL‐G‐F
mice (8‐9 months old) were exposed to either saline or house dust mite (dose: 833μg/kg in saline) every alternate day for 16 weeks. Mice were sacrificed at the end of the experiment, and broncho‐alveolar lavage fluid (BALF), blood, and brains were collected. BALF was analyzed for immune cell markers, inflammatory mediators and total protein content. Serum was analyzed for cytokine and soluble Aβ1‐40/42 levels. In addition, brain sections were immunostained for Aβ and GFAP. Finally, frozen hippocampi and cortices were used to perform Aβ ELISAs and cytokine arrays, respectively.

Result

As expected, dust mite exposure increased inflammatory cells, cytokine levels, and total protein content in the BALF from both sexes and genotypes, suggesting induction of a severe asthma‐like condition. This correlated with increased levels of serum cytokines in all dust‐mite exposed groups. Serum from the AppNL‐G‐F
dust mite‐induced asthma group also had significantly increased soluble Aβ1‐42 levels in both sexes. In agreement with this peripheral change, hippocampi from asthma‐induced male and female AppNL‐G‐F
mice demonstrated elevated Aβ plaque load and increased soluble Aβ 1‐40/42 and insoluble Aβ 1‐40 levels. Dust mite exposure also increased astrogliosis in both sexes of AppNL‐G‐F
mice, as indicated by GFAP immunoreactivity. Finally, dust mite exposure‐induced asthma elevated cortical levels of several cytokines in both sexes and genotypes.

Conclusion

Dust mite exposure was responsible for a severe asthma‐like condition in the lungs that exacerbated Aβ pathology, astrogliosis, and cytokine changes in the brains of male and female App
NL‐G‐F mice. Defining mechanisms of asthma effects on the brain may provide a novel therapeutic approach for both asthma and AD.
Psychotropic polypharmacy in people with neuropsychiatric symptoms referred to an Australian dementia support service
Authors: Atee Mustafa , Andreotta Matthew , Morris Thomas , Alford Marie
Published: December 2022

Background

Despite limited evidence, psychotropics, such as antipsychotics are commonly used to treat neuropsychiatric symptoms (NPS) in people living with dementia. There are safety concerns on the use of antipsychotics, but co‐prescribing multiple classes of psychotropics (psychotropic polypharmacy) may have a greater and more serious harm to this group. This includes sedation‐induced falls, delirium, hospitalizations, and mortality.

In Australia, people with significant NPS, such as agitation and aggression can be referred for free 24/7 support and advise to a national behavior dementia‐specific support service known as Dementia Support Australia (DSA). The aim of this study is to describe the prevalence of psychotropic polypharmacy in DSA referrals.

Method

We used a sample of medication charts from the DSA database to estimate the prevalence of psychotropic polypharmacy in referrals between January and November 2020. A descriptive analysis of psychotropic use was based on the grouping of the World Health Organization Anatomical Therapeutic Classes (ATCs), which included seven classes: antipsychotics, antidepressants, anxiolytics, opioid analgesics, hypnotics, anticonvulsants, and anti‐dementia drugs. Psychotropic polypharmacy was defined as the concomitant use of ≥2 psychotropics overall, whether it is within the same class, subclass, or cross‐class.

Results

Of the 137 referrals [M = 83.6 (SD = 8.5) years of age; 54.0% female], 28 referrals were prescribed medications that could not be nearly categorized into the ATCs (e.g., ibuprofen). For the remaining 109 referrals included in analysis, polypharmacy was common (n = 82, 75.2%; Figure 1A). Polypharmacy was especially common for referrals who were prescribed anxiolytics (n = 25, 100% prescribed additional medication), anticonvulsants (n = 27, 96.4% prescribed additional medication), or anti‐dementia (n = 25, 96.2% prescribed additional medication) medications. Of the 36 different psychotropic medications prescribed to referrals, 23 (63.9%) were prescribed exclusively with additional medications. The most common co‐prescriptions (Figure 1B) were antidepressants+antipsychotics (n = 6, 5.5%), anti‐dementia+opioid analgesic (n = 4, 3.7%), antidepressants+antipsychotics+hypnotics (n = 4, 3.7%), and antipsychotics+hypnotics (n = 4, 3.7%).

Conclusion

Psychotropic polypharmacy is common in people with dementia related NPS who require external behavioral support. Deprescribing psychotropics should be considered a priority in this group as the risks of these agents outweigh their benefits.
Post synaptic density 95 (PSD95)–Actin interaction: A critical regulator of synaptic strength and plasticity in Alzheimer’s disease pathology
Authors: P A Haseena , Kommaddi Reddy Peera , Ravindranath Vijayalakshmi
Published: December 2022

Background

PSD95 serves as a scaffolding protein to several neurotransmitter receptors, signal transduction components, and adhesion molecules at the synapse. It is a potential regulator of synaptic strength and plasticity by regulating glutamatergic receptor trafficking, which is impaired in AD. PSD95 interacts directly with NMDA receptors while the interactions with AMPA receptors are through an auxiliary subunit TARPs. Actin cytoskeleton is highly enriched at the synapse. However, the interaction of PSD‐95 – actin and its consequences in synaptic transmission is not understood. Therefore, we investigated the critical role of PSD‐95 association at the synapse with actin and its impact on AMPA and NMDA receptors using AD mice.

Methods

Synaptosomes were isolated from adolescent and middle aged wildtype and APP/PS1 mice. Immunoprecipitation was performed using the synaptosomes and F‐actin fractions with anti‐PSD95 antibody followed immunoblotting against glutamatergic receptor subunit antibodies and actin antibody. Statistical comparisons between two groups were performed with the two‐tailed unpaired Mann–Whitney U test.

Results

PSD95 association with actin is detected in synaptosomes isolated from adolescent and middle aged WT and APP/PS1 mouse brain cortex. We found that PSD95‐actin association is significantly decreased in middle aged APP/PS1 mice compared with WT while it remains unaffected in the F‐actin fraction of synaptosomes in APP/PS1 mice. Then, we examined the levels of AMPA and NMDA receptor subunits in APP/PS1 mice. GluA1 and GluA2 subunits of AMPAR are significantly decreased in middle aged but not in adolescent APP/PS1 mice in comparison to age matched WT mice. Protein levels of GluN1 and GluN2B subunits are significantly decreased in both adolescent and middle aged APP/PS1 mice, while GluN2A levels are reduced only in adolescent mice. We detected that PSD95 is physically associated with both AMPAR and NMDAR subunits and this association with GluA1 subunit is affected only in middle aged APP/PS1 mice. Interestingly, interaction of NMDAR subunits (GluN1 and GluN2B) with PSD‐95 is greatly enhanced at adolescent APP/PS1 mice even though these subunit protein levels are significantly diminished.

Conclusion

Our findings indicate that perturbation of PSD95‐actin association and glutamatergic receptors in AD leads to synaptic dysfunction. It may have critical implications in defective glutamatergic neurotransmission.
A head‐to‐head comparison of plasma phosphorylated tau assays in the real‐world memory clinic
Authors: Suárez‐Calvet Marc , Ashton Nicholas J. , Puig‐Pijoan Albert , Milà‐Alomà Marta , Fernández‐Lebrero Aida , García‐Escobar Greta , González‐Ortiz Fernándo , Kac Przemyslaw Radoslaw , Brum Wagner Scheeren , Benedet Andréa Lessa , Rodriguez Juan Lantero , Day Theresa A. , Dage Jeffrey L. , Vanbrabant Jeroen , Stoops Erik , Vanmechelen Eugeen , Triana‐Baltzer Gallen , Moughadam Setareh , Kolb Hartmuth C. , Ortiz‐Romero Paula , Karikari Thomas K , Minguillón Carolina , Sánchez Juan José Hernández , Navalpotro‐Gómez Irene , Grau‐Rivera Oriol , Manero Rosa María , Puente‐Periz Víctor , de la Torre Rafael , Roquer Jaume , Zetterberg Henrik , Blennow Kaj
Published: December 2022

Background

Several blood phosphorylated tau (P‐tau) species (P‐tau181, P‐tau217, and P‐tau231) have shown high accuracy to detect AD pathology, but a direct comparison of the main blood P‐tau assays in a real‐world memory clinic is needed. The main aim of this study is to perform a head‐to‐head comparison of 9 plasma Tau assays and determine their accuracy to discriminate between symptomatic AD from non‐AD.

Method

This is an observational and cross‐sectional study in the BIODEGMAR cohort, which includes patients presenting with cognitive complaints at the Cognitive Decline and Movement Disorders Unit of Hospital del Mar (Barcelona, Spain). Patients were classified into an AD CSF profile group or a non‐AD CSF profile group according to their CSF Aβ42/P‐tau181 ratio (Lumipulse, Fujirebio), and the discrimination accuracy of 9 plasma Tau assays was tested. All plasma samples were treated identically and measurements were performed in a blinded fashion.

Result

A total of 197 participants (109 women [55.3%]; mean [SD] age, 72.3 [5.83] years), were investigated. All plasma Tau biomarkers were significantly higher in the AD CSF profile group than in the non‐AD CSF profile group. For plasma Tau biomarkers, the largest effect sizes were found in plasma Janssen P‐tau217 (r = 0.76), Lilly P‐tau217 (r = 0.73), ADx P‐tau181 (r = 0.73), Lilly P‐tau181 (r = 0.68), and UGot P‐tau231 (r = 0.63). All plasma Tau biomarkers significantly discriminated between patients with an AD CSF profile group from those with a non‐AD CSF profile. The AUC of plasma Tau biomarkers were the following (from highest to lower): Janssen P‐tau217 (0.96; 95% CI, 0.93‐0.99), ADx P‐tau181 (0.94; 95% CI, 0.91‐0.97) and Lilly P‐tau217 (0.94; 95% CI, 0.90‐0.98), Lilly P‐tau181 (0.91; 95% CI, 0.87‐0.96), UGot P‐tau231 (0.88; 95% CI, 0.83‐0.93), Quanterix P‐tau181 (0.80; 95% CI, 0.73‐0.87), UGot P‐tau181 (0.80; 95% CI, 0.73‐0.87), Lilly Total‐tau (0.73; 95% CI, 0.65‐0.81), and ADx P‐tau231 (0.66; 95% CI, 0.58‐0.74).

Conclusion

The findings indicate that there are several plasma P‐tau biomarkers that can be used in a memory clinic setting as a stand‐alone biomarker to detect AD pathology in a diverse group of patients presenting with cognitive complaints.
Validity of a contactless device for long term monitoring of sleep in a heterogenous group of older men and women
Authors: Ravindran Kiran K.G. , Monica Ciro della , Atzori Giuseppe , Lambert Damion , Revell Victoria Louise , Dijk Derk‐Jan
Published: December 2022

Background

The incidence of sleep disturbances increases with normal aging and is highly prevalent among people living with dementia (PLWD). To facilitate management and improvement of sleep quality in PLWD, validated unintrusive contactless technologies for long term objective monitoring of sleep are needed. Here we evaluate the ability of a contactless sleep tracker to accurately determine Time in Bed (TIB), Wake vs Sleep and Sleep stages (wake, light, deep, and REM sleep).

Method

We deployed the Emfit (Emfit QS), a contactless sleep tracker placed under the mattress. The Emfit uses ballistography to estimate respiration and heart rate and sleep stages. We collected data from 16 participants (Age: Mean‐72.12; SD‐4.6 years [6F:10M]) at home for a 14‐day period followed by a single overnight laboratory polysomnography (PSG) sleep assessment. The Emfit outputs a) timeseries at 30 s intervals (four sleep stages) and b) overnight summary sleep parameters. Sleep staging and sleep parameter estimation by Emfit was compared to, a) in‐lab gold standard PSG, and b) at‐home wristworn accelerometer (Actiwatch spectrum (AWS)) and sleep diary (SD) data. The epoch‐to‐epoch sleep staging concordance of Emfit was estimated over the total recording interval (∼10hrs) of the PSG for the laboratory session and between 1800hrs and 1200hrs for each SD entry for the home recordings. The concordance analysis for the sleep parameters, bed entry and exit times were performed using the summary data automatically generated by Emfit.

Result

The concordance between the four‐class sleep staging of the Emfit and PSG was poor (Figure 1). The two class (sleep/wake) analysis (Table 1) showed high sleep classification accuracy (sensitivity) but poor wake classification accuracy (specificity) compared to PSG. The sleep parameter estimates of Emfit also showed poor agreement with PSG (Figure 2). The home analysis indicated excellent accuracy for Time in Bed (TIB) (i.e., the bed entry and exit times) as registered by the SD (Table 2) and total sleep time (TST) for both sleep diary and AWS (Figure 3).

Conclusion

: The contactless sleep tracker provides accurate information about Time in Bed (TIB), but there is a lack of consensus of the sleep state classification with the PSG.
CSF proteome profiling reveals novel specific diagnostic biomarkers for Dementia with Lewy bodies
Authors: Campo Marta Del , Vermunt Lisa , Peeters Carel F.W. , Hok Yanaika S. , Lleó Alberto , Alcolea Daniel , van Nee Mirrelijn , Chen‐Plotkin Alice , Irwin David J. , van der Flier Wiesje M. , Lemstra Afina W. , Teunissen Charlotte E.
Published: December 2022

Background

Diagnosis of dementia with Lewy bodies (DLB) remains challenging and biomarkers discriminating DLB from Alzheimer’s disease (AD) are highly needed. We aimed to establish the specific cerebrospinal fluid (CSF) proteomic changes that underlie DLB and to identify translatable diagnostic biomarkers.

Methods

Proximity extension‐based multiplex immunoassays were used to measure 665 proteins in 534 CSF samples from patients with Dementia with Lewy bodies (n=109), AD‐dementia (n=235) and cognitively‐unimpaired controls (CON, n=190) from the Amsterdam Dementia cohort (ADC) and Penn University. An additional multicenter cohort (n=307) from ADC and SPIN was used for validation of custom assays. A positive/negative AD CSF profile supported the diagnosis of AD and CON respectively.

Results

Nested linear models identified 97 CSF proteins with altered abundance in DLB compared to controls (p<0.05). After comparison with the AD CSF proteome, we observed that 52 of these proteins (54%) were especially associated to DLB (e.g. DDC, GH, FCER2, MMP1), while 15 proteins (16%) showed opposite changes to those detected in AD patients (CRH, MMP3). The protein with the highest fold‐changed observed in DLB was L‐amino acid decarboxylase (DDC; >1.5 fold‐change vs.CN or AD; q<1E‐16), an enzyme involved in dopamine biosynthesis. DDC could optimally discriminate DLB from controls and AD patients (AUC: 0.91 and 0.81 respectively). Using penalized generalized linear modelling we identified a panel of 7‐CSF markers including DDC that could discriminate DLB from AD patients with high accuracy (AUC: 0.93, 95%CI: 0.86‐0.98), which have been successfully translated into customized multiplex assays (correlations > 0.84 with discovery measurements).

Conclusions

We unveil CSF changes specifically related to DLB and identified a panel of 7‐CSF markers associated to several aspects of DLB pathophysiology that enables discrimination of these dementia types with high accuracy. Multiplex custom assays containing these markers are currently being clinically validated in independent cohorts for their potential use in diagnostic settings or clinical trials.
Sedation‐associated medications at dementia diagnosis, their receptor activity, and associations with adverse outcomes in a large clinical cohort
Authors: Mbazira Agnes , Bishara Delia , Perera Gayan , Rawlins Elizabeth , Webb Silas , Archer Matthew , Balasundaram Bharathi , Shetty Hitesh , Tsamakis Konstantinos , Taylor David , Sauer Justin , Stewart Robert , Mueller Christoph
Published: December 2022

Background

We aimed to investigate whether sedative medications are associated with adverse outcomes in people with dementia, and whether specific characteristics of these medications predict a higher risk of harm.

Method

A retrospective cohort study was carried out of 15,210 patients diagnosed with dementia between 2008 and 2017 in South London. From recorded medications at dementia diagnosis, we ascertained those with drowsiness listed as a side effect (termed ‘sedative’ hereafter) and subdivided them by frequency and strength of sedation, receptor profile, half‐life and whether they were psychotropics. Multivariable Cox regression models were applied to determine risk of mortality and emergency hospitalisation, and generalised estimating equations to investigate cognitive decline. Final models were adjusted for 19 potential confounders, including measures of physical and mental health, functioning and central anticholinergic burden.

Result

At diagnosis 70.4% of patients with dementia were receiving at least one sedative medication. Median survival time was 4.0 years and median time to first hospitalisation 1.4 years. After controlling for potential confounders, receipt of any sedative medication at dementia diagnosis was associated with accelerated cognitive decline and a higher hospitalisation risk, but only medications with a cautionary warning yielded an increased mortality hazard. Medications acting through gamma‐aminobutyric acid agonism, psychotropic sedatives and those with a short half‐life were associated with a higher risk of mortality. Gamma‐aminobutyric acid agonists, N‐methyl‐D‐aspartate receptor antagonists and non‐psychotropic sedatives were associated with an increased hospitalisation risk. Alpha‐1 antagonist, antihistamines, N‐methyl‐D‐aspartate receptor antagonists, psychotropic sedatives, and those with shortest or longest half‐life were associated with accelerated cognitive decline.

Conclusion

Receipt of any sedative agent was associated with hospitalisation and accelerated cognitive decline. Differences in hazard appear to exist between frequency/strength of sedation, receptor profiles, half‐life, and prescribing indication. These differences should be taken into consideration in medication reviews at the time of dementia diagnosis.
Psychosocial Correlates and Perceived Needs of Family Caregivers of Persons Living with Dementia in India.
Authors: Vasanthra Cicil R , Thirumoorthy A , Antony Sojan , Prasad Krishna , Rao Girish N , PT Sivakumar
Published: December 2022

Background

In India, caregivers of persons living with dementia (CGPwD) often have limited access to dementia care resources. The aim of the study is to understand and deliver psychosocial interventions based on the perceived needs of the CGPwD in accordance with their socio‐cultural background and clinical characteristics of the persons with Dementia (PwD).

Method

A sample of 32 CGPwDs attending a Dementia clinic at the NIMHANS, India, between July 2021 – October 2021 was chosen purposively. Cross‐sectional in‐depth interviews were carried out along with Zarit Burden Interview, (Zarit et al., 1980) and Hindi Mental Status Examination (Ganguli et al., 1995).

Result

The mean age of the CGPwD was 42.5 ± 8.5 years with MMSE score 9±7 indicating moderate to severe dementia. Those caregivers who spent more than 6 hours per day towards day‐to‐day caregiving brought out need for information about the illness seeking clarity about mental health care, support in Activities of daily living (ADLs), managing behavioural and psychological symptoms of Dementia (BPSD) and sharing of caregiver responsibilities, whilst those caregivers who took health related decisions for the PwD where concerned about problems associated with instrumental activities of daily living (iADLs), availability and affordability of caregiving resources such as day care, assisted living options, welfare services. Further results will be presented.

Conclusion

: The perceived needs of CGPwD vary based on severity of illness, socio‐economic status of the CGPwD, age of onset of illness, social support network, relationship between the caregiver and person living with Dementia, spiritual values, readiness to participate in support programs, and much more. Though mental health professionals can develop broader themes for intervention, individualised interventions may warrant poor rates of attrition.

References

Zarit, S. H., Bach‐Peterson, J., & Reever, K. E. (1980). Burden interview. The gerontologist.

Ganguli, M., Ratcliff, G., Chandra, V., Sharma, S., Gilby, J., Pandav, R., … & Dekosky, S. (1995). A Hindi version of the MMSE: the development of a cognitive screening instrument for a largely illiterate rural elderly population in India. International Journal of Geriatric Psychiatry, 10(5), 367‐377.
The Role of Sigma‐1‐Receptor in Endoreticulum Stress and Alzheimer's Disease.
Authors: Nguyen Thinh , Flemming Kayla , Chudalayandi Prakash , Bergeron Richard
Published: December 2022

Background

One evident hallmark of Alzheimer's Disease (AD) is the irregular accumulation of proteins such as Aβ and pTau. This accumulation could alleviate ER stress and trigger an integrated signaling cascade called the unfolded protein response (UPR). UPR reduces the number of misfolded proteins and further inhibits abnormal protein accumulation. Targeting ER stress may therefore be an effective treatment for AD. One protein of interest that plays a role in modulating ER stress is the Sigma‐1 receptor (Sig1R). Sig1R agonists have been shown to be neuroprotective and anti‐amnesic in AD mouse models. However, the mechanism of action remains largely unknown.

Method

In our study, we use primary MEF cells derived from Wild‐type and Knock‐out Sig1R mouse models to examine the role of Sig1R in ER stress. We treated cells with an acute ER stressor, DTT, and measured transcript levels of target genes under the UPR branches. Furthermore, we used Chromosomal Immunoprecipitation (ChIP) to identify regulators of SIG1R gene during stress.

Result

We observed that the loss of Sig1R compromised the PERK pathway. KO MEFs had a slow recovery from stress suggesting Sig1R plays a role in re‐establishing homeostasis following stress. Following DTT treatment, mRNA and protein levels of Sig1R increase significantly over the course of recovery. ChIP uncovered three CHOP, a major player in the UPR, binding sites within the promoter of SIG1R, and each site had a distinct temporal binding pattern over the course of cell recovery. This increase in binding correlates with an increase in Sig1R expression. This showed that Sig1R is a chaperone downstream of CHOP, and that the up‐regulation of Sig1R might be crucial in re‐establishing homeostasis. Finally, our imaging data showed an increase in localization of Sig1R with extracellular vesicles. We further hypothesized that the high expression of Sig‐1R may have a role in the removal of misfolded proteins, perhaps Aβ. Therefore, we have ongoing experiments looking at the effect of Aβ on our models.

Conclusion

Our study has the potential to unravel the implications of Sig1R in AD by showing that it is transcriptionally and translationally regulated in response to stress induced by misfolded proteins.
The novel FKBP51‐Hsp90 interaction inhibitor attenuates high‐fat diet induced cognitive impairment
Authors: Wang Lisha , Wojcieszak Jakub , Kumar Rajnish , Pavlov Pavel F. , Winblad Bengt
Published: December 2022

Background

Obesity increases the risk of several chronic diseases, such as type 2 diabetes mellitus, insulin resistance, and Alzheimer disease. As one of the co‐chaperones of heat shock protein 90 (Hsp90), FK506‐binding protein 51 (FKBP51) is an important regulator of metabolic and cognitive dysfunction. FKBP51 knockout mice are resistant to diet‐induced obesity, exhibit elevated glucose and insulin tolerance and have less endogenous tau. FKBP51 overexpression preserves tau and impairs spatial reversal learning and memory. Our group has identified a new family of FKBP51 inhibitors that can disrupt FKBP51‐Hsp90 interactions. Previous study has shown that our inhibitors can dose‐dependently reduce lipid accumulation in adipocytes differentiated from primary human mesenchymal stem cells and stimulate neurite outgrowth in differentiated neuroblastoma SH‐SY5Y cells. This study aims to investigate the potential roles of our inhibitors on metabolic and cognitive dysfunction in vivo.

Methods

Pharmacokinetic studies have been performed at first. Plasma and brain samples were collected and analyzed by liquid chromatography‐mass spectrometry. Male C57BL/6J mice were fed either the control or high‐fat diet (HFD) for 4 weeks and then treated with vehicle or inhibitor E8 (20 mg/kg, s.c.) and their respective diets for another 4 weeks. Behaviors, body composition measuremnets by EchoMRI, fasting glucose/insulin detections and glucose/insulin tolerance tests were performed during the last week. Hippocampus was collected for western blot, RNA sequencing and quantitative real‐time PCR analysis.

Results

After subcutaneous injection, E8 can be quickly absorbed into the blood and penetrate the blood‐brain barrier. In HFD model, E8 can attenuate the impairment of locomotor activity and short‐term memory. But it could neither reduce body weight gain nor improve insulin sensitivity and glucose/insulin tolerance. In the hippocampus, E8 reduces the elevated p‐tau (Ser214)/tau levels induced by HFD but does not show any effects on insulin signaling. It suggests that E8 reverses the behavioral impairments independently of metabolic regulation in vivo. The underlying mechanisms were further investigated by RNA sequencing and quantitative real‐time PCR analysis.

Conclusion

We showed that inhibiting FKBP51‐Hsp90 interactions with small molecules provides novel therapeutic targets on cognitive dysfunction in obesity.
Tau Loss of Function, by Deletion or Aggregation, Contributes to Peripheral Insulin Resistance
Authors: Al‐Lahham Rabab , Mukherjee Abhisek , Dinamarca Nicolas Mendez , Banerjee Victor , Soto Claudio
Published: December 2022

Background

Epidemiological association between Alzheimer’s disease (AD) and type 2 diabetes is a critical health concern that has not been resolved yet at the molecular mechanistic level. While brains of AD patients and AD transgenic mouse models display impaired insulin signaling, there is no clear understanding of the role of peripheral insulin resistance in the pathogenesis of AD. Moreover, alterations in key insulin signaling proteins have been also implicated in AD, among which GSK‐3β, is also one of the important kinases for the phosphorylation of the microtubule‐associated protein tau (tau), one of the pathological hallmarks of AD. The goal of this study is to determine the role of systemic insulin resistance in the pathophysiology of AD by testing the hypothesis that functional tau is important for peripheral insulin sensitivity, and its deletion or loss‐of‐function promotes peripheral insulin resistance.

Method

Primary hepatocytes were isolated from transgenic mouse models (P301L, tau KO), and wild type mice (C57BL/6), and their insulin sensitivity was assessed by an insulin challenge, using biochemical analysis of insulin signaling markers, and glucose uptake assays. To confirm the involvement of tau, we treated wild type hepatocytes with tau aggregates and investigated their effect on insulin sensitivity. To investigate the involvement of p38 MAPK, a stress‐response protein, we pre‐treated wild type hepatocytes with a pharmacological inhibitor of p38 prior to tau aggregates treatment.

Result

We found that tau deletion or loss‐of‐function promotes peripheral insulin resistance as seen by the inhibition of insulin signaling proteins and the reduction of glucose uptake into primary hepatocytes isolated from tau KO and P301L mice, respectively. We also found that sub‐toxic exposure of wild‐type primary hepatocytes to tau aggregates resulted in inhibition of insulin signaling and glucose uptake, in a dose‐dependent manner. Our data also show that p38 MAPK may be involved in tau aggregates‐induced inhibition of insulin signaling.

Conclusion

This is the first study testing the potential role of tau in peripheral insulin resistance at the cellular level using multiple mouse models. Our findings suggest that functional tau is required for insulin sensitivity, therefore, any loss‐of‐function by aggregation or deletion would result in insulin resistance.
Comparison of the Telephone‐Montreal Cognitive Assessment (T‐MoCA) and Telephone Interview for Cognitive Status (TICS) as Remote Screening Tests for Early Alzheimer’s Disease.
Authors: Chappelle Sheridan D. , Gigliotti Christina , Leger Gabriel C. , Peavy Guerry M. , Jacobs Diane M. , Banks Sarah J , Little Emily A , Galasko Douglas R. , Salmon David P.
Published: December 2022

Background

The number of Americans with Alzheimer’s disease (AD) is expected to rise to nearly 14 million by 2060. This alarming number shows a critical need for brief mental status tests that can be administered remotely (e.g., by telephone or videoconferencing) to large numbers of individuals while maintaining the ability to reliably detect cognitive impairment related to AD. Therefore, we sought to validate a recently developed, remotely administered cognitive screening measure, the T‐MoCA, against an established remote measure, the TICS, and prior in‐person clinical and cognitive assessment that provided clinical diagnosis. Relationships with CSF biomarkers of AD were also examined.

Methods

The TICS and T‐MoCA were completed approximately one‐week apart by 215 participants at the UCSD ADRC. Test order was partially counterbalanced. Extensive in‐person clinical and neuropsychological assessment had been completed on average 1.5 years prior and participants classified as cognitively normal (CN; n = 167), mild cognitive impairment (MCI; n = 25) or dementia (n = 23). CSF had been obtained from 79 participants within 48 months of remote testing and levels of Aβ 1–40 and 1–42, phosphorylated tau (p‐tau), and total tau were measured.

Results

TICS and T‐MoCA scores were highly correlated overall (r = .787;p<.001), and moderately within specific MCI (r = .657;p<.001) and dementia (r = .673,p = .001) groups (r = .309, p<.001 for CN only). Groups differed significantly on TICS (F(2,212) = 156.66;p<.001) and T‐MoCA (F(2,210) = 143.72;p<.001), with dementia<MCI<NC on both (p’s<.001). TICS and T‐MoCA had excellent ability to discriminate CN from cognitively impaired (i.e., MCI/dementia) with ROC areas under the curve of .889 and .902, respectively. Optimal cut‐off scores were <17/22 for T‐MoCA (90.4% sensitivity, 76.6% specificity) and <34/41 for TICS (91.0% sensitivity, 74.5% specificity). A composite CSF biomarker of AD (total tau/Aβ 1–42 ratio) was negatively correlated with TICS (r = ‐.372;p = .001) and T‐MoCA (r = ‐.480;p<.001).

Conclusion

The T‐MoCA and TICS are valid brief cognitive screening tests with remote administration that can distinguish individuals with cognitive impairment from those who are cognitively normal. The two tests have similar discriminative ability and degree of association with levels of AD biomarkers in CSF. Thus, the T‐MoCA and TICS are promising measures to meet the growing need for remote cognitive screening for AD.
Bulk brain tissue cell type deconvolution with bias correction for single‐nuclei RNA‐seq
Authors: O'Neill Nicholas K , Hu Junming , Stein Thor D. , Zhang Xiaoling , Farrer Lindsay A.
Published: December 2022

Background

Quantifying cell type percentages from bulk brain RNA‐sequencing enables researchers to better understand the components underlying disease pathogenesis. Despite being designed for single‐cell RNA‐sequencing (scRNA‐seq) data, MuSiC deconvolution algorithm can use single‐nuclei RNA‐sequencing (snRNA‐seq) data generated from brain tissue to estimate cell type proportions in bulk brain RNA‐sequencing data but does not fully compensate for sequencing differences between bulk and snRNA‐seq data. We modified MuSiC's gene weighing scheme to compensate for this sequencing bias.

Methods

MuSiC calculates gene weight each iteration using the residual from the previous iteration, gene variation among subjects, and other factors. We calculated the RNA capture rate difference between genes in single‐nuclei and bulk sequencing data and reduced MuSiC’s weight for genes with strong differences. We compared the accuracy of deconvoluted data from MuSiC and our modified algorithm (mMuSiC) by simulating bulk data with seven brain cell types and calculating the concordance correlation coefficient (CCC) between true and estimated cell type percentages. The accuracy of the original and modified deconvolution algorithms was also assessed using human brain dorsolateral prefrontal cortex (DLPFC) bulk RNA‐seq data sets from ROSMAP with subject‐matched immunohistochemistry (IHC) measurements for 69 samples and bulk RNA‐seq from the Framingham Heart Study/Boston University Alzheimer Disease Research Center with subject‐matched microglial (IBA1+) cell density measurements for 163 samples from the same brain region.

Results

mMuSiC improves the concordance correlation coefficients (CCC) between estimated and true cell fractions in our four simulations for each cell type with a p‐value of 0.014. This improvement is especially pronounced for both inhibitory and excitatory neurons, with an average CCC of 0.45 for mMuSiC and 0.22 for MuSiC. In human brain DLPFC bulk RNA‐seq data, our method also improves the CCC between cell fraction estimates and IHC measurements for each cell type tested in ROSMAP, with mMuSiC averaging 0.14 and MuSiC averaging 0.10. The correlation between microglia cell fraction estimates and IBA1+ cell density measurements is also improved in mMuSiC (R=0.33, p=1.5e‐5) over MuSiC (R=0.12, p=0.11).

Conclusion

mMuSiC improves cell fraction estimates of bulk brain RNAseq datain studies using snRNA‐seq. This is particularly useful for brain research where snRNA‐seq is unavailable.
Identification of transcriptional signatures of cognitive resilience using single nucleus RNA sequencing
Authors: Hadad Niran , Telpoukhovskaia Maria , Zhang Jigang , Samuels Michael , Robson Paul , Philip Vivek M. , Kaczorowski Catherine C.
Published: December 2022

Background

It is estimated that a third of the elderly population is not diagnosed with Alzheimer’s disease (AD) due to the absence of cognitive impairment despite carrying risk variants of AD or presenting AD pathology post‐mortem. This suggests that at‐risk individuals may carry protective mechanisms that promote resilience to cognitive impairment, however the underlying molecular processes that promote resilience remain unknown.

Method

To determine transcriptional changes associated with resilience, we profiled the hippocampal transcriptome at the single cell level in 7 resilient and 7 susceptible strains from the AD‐BXD mouse reference panel1, a genetically diverse mouse model of AD that better mimics human AD. Here, we used contextual fear memory paradigm to assess short‐term memory function in AD‐BXDs carrying the 5XFAD mutation. Resilience was defined based on age‐related change in cognitive function relative to that of the entire AD‐BXD population, where strains showing no or lower than average decline were considered resilient.

Result

Using single nucleus RNA‐sequencing, we profiled ∼220 K nuclei from the hippocampal formation and identified 32 cell clusters representing the major cell types in the hippocampus including glutamatergic neurons, GABAergic neurons, astrocytes, oligodendrocytes and microglia. With the exception of GABAergic neurons, transcriptional changes associated with the 5XFAD mutation were greater in susceptible AD‐BXDs. Gene expression changes associated with cognitive resilience were primarily observed in excitatory neurons, specifically in the CA1 and dentate gyrus and were enriched for ribosomal genes and nuclear encoded mitochondrial genes. In attempt to infer potential ligands that regulate resilience‐associated transcriptional changes we used a ligand‐target interaction analysis and predicted potential ligands regulating resilience programs in excitatory neurons.

Conclusion

Our findings demonstrate that the rate of cognitive decline is concomitant with increased transcriptional changes associated with the 5XFAD mutation across cell types in the hippocampus. We show that molecular programs associated with resilience in excitatory neurons are enriched in protein metabolism, cellular respiration and translation, possibly indicating a response to energy demand and maintenance of cellular homeostasis.

Neuner SM, Heuer SE, Huentelman MJ, O'Connell KMS, Kaczorowski CC. Harnessing Genetic Complexity to Enhance Translatability of Alzheimer's Disease Mouse Models: A Path toward Precision Medicine. Neuron. 2019.
Selection Factors Influencing Participation in National Alzheimer’s Coordinating Center (NACC) Studies Compared to the Nationally Representative Health and Retirement Study (HRS)
Authors: Evangelista Nicole D. , Renteria Miguel Arce , Mobley Taylor M , Fox‐Fuller Joshua T. , Minto Lex , Avila Justina F , Deters Kacie D , Medina Luis D , Bettcher Bri M
Published: December 2022

Background

Racial/ethnic disparities in ADRD are well documented such that prevalence of ADRD and known risk factors (e.g., cardiovascular disease, educational attainment) disproportionately impact Black and Latinx populations compared to their White counterparts. To generalize findings on the mechanisms and disease course and mitigate racial/ethnic disparities in ADRD, it is critical that diverse populations are well represented in studies of ADRD. We examined selection factors across racial/ethnic groups included in National Alzheimer’s Coordinating Center data (NACC) compared to the general U.S. population using data from the Health and Retirement Study (HRS).

Method

Analyses included baseline NACC data from 33,998 participants (Mage = 74.1yrs±8.0; Medu = 15.5±6.9; 56.7% women) and the 2010 wave of HRS weighted up to the 2010 US population aged 60+ years (weighted n = 48,726,070; Mage = 71.3yrs; Medu = 12.9yrs; 54.3% women). We assessed covariate balance between NACC and the 2010 US population aged 60+ by calculating standardized mean differences across harmonized sociodemographic factors, self‐reported health characteristics, depressive symptoms, and subjective memory concerns stratified by race/ethnicity. Standardized mean differences greater than +/‐ 0.25 were considered strong selection factors into NACC.

Result

Across all racial/ethnic groups, NACC participants were more likely to be older, have higher educational attainment, and report subjective memory concerns and hearing difficulties compared to the 2010 US population aged 60+ years (Figure). Standardized mean differences for age, educational attainment, and memory concerns were larger among non‐Latinx Whites compared to differences among non‐Latinx Black and Latinx participants. There was greater representation of non‐Latinx Black women in NACC, and non‐Latinx Black and Latinx NACC participants were less likely to endorse depressive symptoms. Additionally, results suggested non‐Latinx White participants were less likely to report diabetes and hypertension compared to their 2010 aged 60+ US population counterparts.

Conclusion

Results suggest that NACC participants are not representative of the U.S. population in key demographic and health factors and self‐reported memory concerns. These selection factors differed across racial/ethnic groups and are suggestive of selection bias. Future studies should leverage statistical tools that aimed at generalizing findings to general populations. Studies should also consider mitigating these sources of bias through inclusive recruitment efforts across Alzheimer’s Disease Centers to improve generalizability.
Word Generation from Letter and Semantic Categories Across the Alzheimer’s Disease Spectrum
Authors: Menendez Natalia R. , Smirnov Denis S. , Thomas Kelsey R. , Bondi Mark W. , Gollan Tamar H. , Jacobs Diane M. , Galasko Douglas R. , Salmon David P.
Published: December 2022

Background

Individuals with mild dementia or mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) often have verbal fluency deficits with greater impairment in generating exemplars from a semantic category (e.g., “animals”) than words that begin with a particular letter (e.g., ‘F’). This may reflect early development of pathology in cortical regions mediating semantic knowledge/organization required to efficiently generate words from a conceptually‐related set of exemplars. We sought to determine if this word generation deficit and discrepancy between category and letter fluency emerges in the preclinical stage of AD.

Participants and Methods

Semantic and letter fluency tasks were completed by 394 participants. Correct words generated in one minute from each category was summed across animals, fruits, and vegetables (AFV), and across letters ‘F’, ‘A’, and ‘S’ (FAS). CSF was obtained within one year of the fluency tasks and levels of Aβ40, Aβ42, phosphorylated tau (p‐tau), and total tau were measured. Participants were classified as cognitively normal (CN) with negative AD biomarker (CN‐Neg; n = 179), CN with positive AD biomarker (tau/Aβ42 ratio>.609) (CN‐Pos; n = 59), MCI (all biomarker positive; n = 46), and AD dementia (all biomarker positive; n = 110).

Results

A Group X Task repeated measures ANOVA (adjusting for age and education) showed participants generated more correct words for AFV than FAS (F(1,380) = 20.44; p.001), there was a general stepwise decline in words generated across the AD spectrum (AD<MCI<CN‐Pos = CN‐Neg) (F(3,380) = 144.13; p.001), and this decline was greater on AFV than FAS (interaction F(3,380) = 18.59; p.001). CN‐Pos and CN‐Neg did not differ in correct words generated on either task, but AFV (r = ‐.304; p = .018) and FAS (r = ‐.290; p = .025) scores were negatively correlated with levels of p‐tau in amyloid positive (Aβ42/40 ratio<.056), but not amyloid negative, CN individuals.

Conclusions

Although word generation was not impaired in the CN‐Pos group, a negative relationship with CSF p‐tau in the context of amyloid positivity suggests that changes in verbal fluency may be emerging in preclinical AD. A similar relationship with p‐tau for letter and semantic fluency implies that mechanisms common to both tasks (e.g., initiation of effortful retrieval) are affected earlier than mechanisms with greater specificity to the semantic fluency task (e.g., semantic knowledge/organization).
Neuropathological validation of plasma GFAP
Authors: Benedet Andréa Lessa , Smirnov Denis S. , Ashton Nicholas J. , Hiniker Annie OF , Simrén Joel , Rodriguez Juan Lantero , Zimmer Eduardo R , Zetterberg Henrik , Blennow Kaj , Galasko Douglas R.
Published: December 2022

Background

Glial fibrillary acidic protein (GFAP) is an astrocytic marker that has been recently associated with fluid and imaging biomarkers of amyloid and tau pathologies in the Alzheimer’s disease (AD) spectrum. Plasma GFAP has also shown to be a strong indicator of early brain amyloidosis in preclinical AD. However, it remains to be confirmed how plasma GFAP associates with neuropathological hallmarks of AD and which pathological entities are being reflected by this plasmatic marker.

Method

Plasma GFAP concentrations were measured using a commercial Simoa assay on participants of the UCSD Shiley‐Marcos Alzheimer’s Disease Research Center (ADRC), consisting of 271 participants with brain autopsy data. Amyloid and tau pathologies were assessed following the CERAD, Braak and NIA‐Reagan criteria, as well as with tangle and plaque counts (147 participants). Cerebral amyloid angiopathy (CAA) was graded as recommended by NACC Neuropathology Working Group. Non‐AD pathologies were also assessed: Lewy body disease, hippocampal sclerosis, TDP‐43 and vascular pathology. The distribution of GFAP concentration was compared across groups using ANCOVA models adjusting for age and sex, followed by post‐hoc Tukey’s HSD test. The association between GFAP and the pathological indexes was tested using linear models and adjusted by covariates.

Result

Concentrations of plasma GFAP were higher in females as compared to males (P=0.008) and no age effect was observed. GFAP also increased with severity of AD pathological stages (P<0.001), with increased neuritic (P<0.001) and diffuse plaque density or counts (P=0.001), as well as with Braak stages and tangle counts (P<0.05). We found no association between tangle counts and GFAP when accounting for the effect of plaque counts. The presence of co‐pathologies did not affect average GFAP levels. We found no association between GFAP and CAA.

Conclusion

Plasma GFAP showed again here to highly reflect amyloid deposition. Results indicate, however, that this association is due to the accumulation of extra‐cellular amyloid in the form of plaques rather than its deposition in blood vessels. Abnormal accumulation of non‐AD proteins did not show any marked effect on GFAP levels. More detailed analysis, including longitudinal retrospective data, is ongoing.
Cx3cr1 deficiency aggravates Aβ driven neurodegeneration and cognitive decline in a mouse model of Alzheimer's disease.
Authors: Puntambekar Shweta S , Moutinho Miguel , Lin Peter Bor‐Chian , Jadhav Vaishnavi , Tumbleson‐Brink Danika , Balaji Ananya , Benito Martin A , Xu Guixiang , Oblak Adrian L , Reeves Cristian A Lasagna , Landreth Gary E , Lamb Bruce T
Published: December 2022

Background

Despite its identification as a key checkpoint regulator of microglial activation in Alzheimer’s disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau in is not well understood.

Method

Using 4 ‐ and 6‐month old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1‐/‐ mice, we use immunohistochemistry, western blotting, transcriptomic analysis and quantitative real time PCR to investigate accumulation of soluble and insoluble Aβ species, plaque associated microglial activation, synaptic dysregulation and neurodegeneration with disease progression. Flow cytometry based, Aβ uptake assays are used for in‐vivo characterization of the effects of CX3CR1‐signaling on microglial phagocytosis and degradation of methoxy‐X04+ fibrillar Aβ. Lastly, we use Y‐maze testing to analyze the effects of Cx3cr1 deficiency on working memory in 5xFAD mice.

Result

We show that disease progression in 5xFAD;Cx3cr1‐/‐ mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement, along with impaired microglial Aβ phagocytosis and lysosomal acidification in‐vivo. Interestingly, Cx3cr1 deficiency resulted in heighted accumulation of neurotoxic, oligomeric Aβ, which correlated with severe neuritic dystrophy, preferential loss of post‐synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA coupled with real time PCR validation using FACS‐purified microglial cells revealed dysregulated TGFβ responses, inflammatory signaling and oxidative stress responses in 5xFAD;Cx3cr1‐/‐ mice.

Conclusion

In contrast to increased Aβ uptake by Cx3cr1‐/‐ microglia during early disease, Cx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering an accumulation of neurotoxic soluble and insoluble Aβ species with disease progression. Our results indicate that Aβ‐driven microglial dysfunction in Cx3cr1‐/‐ mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory. This study underscores the importance of investigating the time‐dependent role of CX3CR1‐driven microglial responses in AD.