bluuebunny/crossref_metadata_2025 huggingface dataset:
Geo‐cultural influences on the relationship between the CDR and MMSE
Authors: Kamat Rujvi , Appleman Erica R. , Chen Zinan , Stenclik Jessica , Machizawa Sayaka , Feaster H Todd
Published: December 2022

Background

The increasingly global scope of clinical trials in Alzheimer’s disease (AD) has led to the recruitment of subjects from various geo‐cultural regions. Recent studies suggest that commonly used objective measures of cognition such as the MMSE as well as subjective, clinician‐rated global measures such as the CDR might be impacted by cultural and/or linguistic differences. This raises the question regarding the impact of cultural differences on the convergent validity of the CDR and MMSE.

In this analysis, we examined the extent to which the correspondence between the CDR and MMSE varied across seven geo‐cultural regions in multinational AD clinical trials.

Method

This study included electronic CDR (eCDR) and electronic MMSE (eMMSE) data from four multinational AD clinical trials of subjects with Prodromal to Mild AD. Data were collected at screening from seven geo‐cultural regions: East Asia (n = 1916), Eastern Europe (n = 1882), South America (n = 1601), Middle East/Africa (n = 188), North America (n = 9311), Oceania (n = 363), and Western Europe (n = 5174).

Result

Pearson correlations between eCDR Sum of Boxes (SOB) and eMMSE across the 7 geo‐cultural regions ranged from r = ‐.31 (East Asia, Western Europe) to r = ‐.48 (Mideast/Africa). A linear regression model with geo‐cultural regions entered as covariates further demonstrated that the relationship between eMMSE and eCDR SoB scores differed by region (Adjusted R2 = 0.14, p<0.001).

Conclusion

Findings indicate the strength of the correlation between the CDR SOB and MMSE total score varied by geo‐cultural region. These results build on prior findings indicating that CDR SOB and MMSE scores vary across regions independent of each other. A growing body of literature suggests these differences might be due to cultural and/or linguistic factors.
APOE Allele Switching in a Novel Transgenic Mouse Model as a Therapeutic Approach for Alzheimer’s Disease
Authors: Golden Lesley R , Johnson Lance A
Published: December 2022

Background

Individuals homozygous for the ε4 allele of Apolipoprotein E (APOE) face up to a 15‐fold increase in Alzheimer’s Disease (AD) risk. In comparison, those carrying two ε2 alleles have nearly a 99.6% reduction in risk. Given APOE’s strong risk profile and multitude of effects, APOE itself has emerged as a promising therapeutic target. CRISPR‐Cas9 technology has been used to successfully edit APOE in vitro, where iPSC‐derived glia and neurons edited from ε4 to ε3 show pronounced transcriptional and phenotypic changes. However, whether the putatively beneficial effects of switching to APOE2 holds true in in vivo models has yet to be fully determined.

Methods

We developed a novel transgenic mouse model, the APOE “switch mouse” (4S2) which allows for an inducible (CreERT2) transition from expression of ApoE4 to ApoE2. Gene expression, western blotting, ELISA, and mass spectrometry based proteomic analysis were used to confirm that 4S2 mice synthesize full‐length human ApoE4 at baseline (pre‐switch) and full‐length human ApoE2 after tamoxifen administration (post‐switch). Analysis of plasma lipids, metabolomics, and transcriptomic analyses were used to identify downstream, physiological effects of replacing ApoE4 with ApoE2.

Results

Physiological phenotyping, gene expression measures, and proteomic analyses further show that following tamoxifen injection, the inducible switch successfully results in efficient (>98%) recombination and expression of human ApoE2. Global genetic replacement of ApoE4 with ApoE2 results in changes to plasma lipids. Mass spec imaging revealed changes in multiple classes of lipids, while single‐cell and spatial RNAseq analyses shows distinct alterations in glial cell transcriptomes. Together these data suggest a successful transition from ApoE4 to ApoE2 that has broad impact on the glial transcriptome as well as on peripheral and cerebral metabolism.

Conclusions

Our exciting preliminary studies have leveraged this new mouse as a promising model to assess the feasibility and therapeutic window of replacing APOE4 with APOE2, along with any potential off‐target effects. Ongoing studies aim to determine whether cell‐specific replacement of ApoE4 with APOE2 will rescue E4 associated metabolic dysfunction, disease associated gene signatures, and AD pathology. We hope that this new model will be a valuable resource for the AD/APOE research community.
Risk of unexpected mortality is increased by evoked seizures in the APP/PSEN1, but not PSEN2‐N141I transgenic, mouse model of Alzheimer’s disease
Authors: Sanz Aaron Del Pozo , Knox Kevin M , Davidson Stephanie , Lehmann Leanne M , Barker‐Haliski Melissa
Published: December 2022

Background

Patients with early‐onset Alzheimer’s disease (AD) with amyloid precursor protein (APP) duplication are at significantly elevated risk of seizures (Zarea et al, Neurology 2016). Deaths specifically from AD in patients with epilepsy have increased over 200% in the last 20 years (DeGiorgio et al, BMJ Open 2020). The incidence of sudden, unexpected death in epilepsy (SUDEP; Harden et al, Neurology 2017) remains unchanged. The co‐occurrence of epilepsy and AD critically increase risks for mortality yet whether specific AD‐associated risk genes more significantly escalate mortality risk is unclear.

Method

Male and female 2‐month‐old APP/PS1 and wild‐type littermates (WT) of C57Bl/6J mice, were subjected to the corneal kindling model of temporal lobe epilepsy, which is routinely used for antiseizure drug discovery (Barker‐Haliski et al, Neurochem Res 2017). PSEN2‐N141I transgenic mice and WT controls were similarly kindled to assess whether AD‐associated risk factors differentially influence mortality risk. APP/PS1 and PSEN2‐N141I mice (n=5‐10 mice/genotype/sex) were kindled with a twice‐daily subthreshold electrical stimulus (3 sec 60 Hz 1.6‐3 mA current) for 2‐3 weeks until each mouse presented with 5 consecutive Racine stage 5 seizures. Survival during kindling acquisition was compared across all genotypes within sexes. Post‐kindling survival was assessed with each twice‐weekly baseline stimulation for up to 2 months.

Result

Both male and female APP/PS1 mice were more rapidly kindled than WT littermates, whereas male and female PSEN2‐N141I mice were slower to kindle versus WT controls. The survival of fully kindled male, but not female, APP/PS1 mice was significantly different from age‐matched WT littermates (males: X2=8.635, p<0.01; females: X2=3.00, p>0.05). Conversely, there was no difference in post‐kindling mortality for PSEN2‐N141I mice in either sex versus WT controls. The time‐related effects of corneal kindling on serotonin receptor and transporter expression assessed by western blot will be further discussed, with changes in serotoninergic tone known to increase mortality risk in patients with epilepsy alone.

Conclusions

Our study suggests that discrete AD‐associated risk factors differentially increase mortality risk in the context of chronic seizures in young adult mice. Future studies are necessary to determine whether AD‐specific genetic risk factors influence seizure‐induced mortality and identify preventative agents.
Ranolazine Effectively Ameliorated Brain Pathologies and Cognitive Decline in Rats with Trastuzumap‐Induced Chemobrain
Authors: Chunchai Titikorn , Arinno Apiwan , Ongnok Benjamin , Pantiya Patcharapong , Khuanjing Thawatchai , Prathumsap Nanthip , Maneechote Chayadom , Pintana Hiranya , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2022

Background

Chemotherapy can increase survival rate of cancer patients. One of the chemotherapeutic drugs for breast cancer patients is trastuzumap (Trz). Chemotherapy not only helps to kill cancers, but it also causes several adverse effects in the patients, particularly in the brain, known as chemobrain. Chemobrain has been characterized by cognitive decline with brain mitochondrial dysfunction, hippocampal microglial activation, and loss of dendritic spines. Although several types of chemotherapy induce chemobrain, Trz‐induced chemobrain are not clearly elucidated. Ranolazine, a drug that is commonly used to treat the patients with chronic angina, shows benefits on cognitive function in doxorubicin‐induced chemobrain. However, the effects of ranolazine on brain mitochondrial function, hippocampal microglial function, hippocampal dendritic spines, and cognitive function in Trz‐induced chemobrain have never been investigated.

Methods

Eighteen male Wistar rats were randomly divided into two groups including control group (0.9% NSS, intraperitoneal (i.p.) injection, n=8) and Trz‐treated group (4 mg/kg for 7 days, i.p. injection, n=16). All Trz‐treated rats were randomly divided into two subgroups (n=8/ subgroup) to receive either vehicle (0.9% NSS, daily via oral gavage) or ranolazine (305 mg/kg/day, daily via oral gavage). At the end of experiment protocol, cognitive function was measured, and brains were obtained for further molecular investigation.

Results

The results demonstrated that vehicle‐treated Trz‐rats significantly increased brain mitochondrial ROS production, increased brain mitochondrial membrane potential change, and increased brain mitochondrial swelling, suggesting brain mitochondrial dysfunction (p<0.05, Figure 1). These parameters were attenuated in ranolazine‐treated Trz‐rats (p<0.05, Figure 1). In addition, the microglial activation was found in vehicle‐treated Trz‐rats as indicated by increased the number of microglial cells, which was suppressed by the ranolazine treatment (p<0.05, Figure 1). Consistently, the dendritic spine density decreased in vehicle‐treated Trz‐rats, leading to cognitive decline (p<0.05, Figure 1). Ranolazine‐treated Trz‐rats showed an increase in dendritic spine density, resulting in the improvement of cognitive function (p<0.05, Figure 1).

Conclusions

All findings suggest that ranolazine effectively ameliorated cognitive decline in rats with Trz‐induced chemobrain. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for better preventing chemobrain in the future.
Acetylcholinesterase Inhibitor Exerted Neuroprotection Against Trastuzumab‐Induced Chemobrain
Authors: Ongnok Benjamin , Khuanjing Thawatchai , Chunchai Titikorn , Pintana Hiranya , Pantiya Patcharapong , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2022

Background

Chemobrain has recently gained attention as a serious neurobehavioral consequence of chemotherapy in cancer patients. Even well‐recognized among conventional chemotherapeutic agents, trastuzumab (TRZ), an oncogene‐targeted therapy for treating breast cancer, has been shown to intricately caused symptoms of chemobrain elicited by impaired cerebral glucose metabolism and long‐term cognitive function. Noticeably, the inhibition of acetylcholinesterase using donepezil (DPZ), a medication widely used to treat Alzheimer’s disease (AD), possesses several pleiotropic effects including mitochondrial protection and immunomodulation. However, the mechanistic insights regarding the pathophysiology and therapeutic benefit of DPZ have never been holistically determined in a rat model of TRZ‐induced chemobrain.

Method

Fifteen male Wistar rats were randomized to receive either a 0.9% normal saline solution (Control; n=5) or 4 mg/kg of TRZ via intraperitoneal injection for 7 consecutive days. Then, TRZ‐treated rats were subdivided into 2 groups to receive either drinking water (TRZ, n=5) or 5 mg/kg of DPZ (TRZ+DPZ; n=5) via oral gavage as co‐treatment with TRZ for 7‐day duration. After cessation of the treatment paradigm, cognitive performance was assessed using the novel object location task (NOLT). The brain tissues were obtained for further molecular investigation.

Result

TRZ‐treated rats showed impaired long‐term spatial memory as demonstrated by a reduction of preference index in the NOLT (Figure A). Systemic TRZ administration compromised mitochondrial anti‐oxidant capacity (Figure B) and potentiated the activation of mitochondrial‐fission related protein. Furthermore, the upregulation of neuroinflammation was observed in TRZ‐treated rats presented by increased TNF‐α mRNA level (Figure C) and microglial morphological changes into neurotoxic amoeboid‐shaped (Figure D). Additionally. Administration of TRZ triggered the phosphorylation of Tau protein (Figure E) and reduced dendritic spine density in CA1 region (Figure F). Strikingly, co‐administration with DPZ effectively rescued cognitive performance of TRZ‐treated rats by improving mitochondrial anti‐oxidant capacity, reducing mitochondrial fission, mitigating neuroinflammation and microglial polarization, attenuating Tau hyperphosphorylation, and preserving dendritic spine density (Figure A‐F).

Conclusion

These findings suggested that DPZ exerted neuroprotective effects against TRZ‐induced chemobrain. Our findings pave the way for parasympathetic activation using DPZ as a therapeutic approach in the prevention of chemobrain in patients who received chemotherapy in the future.
Vascular primary cilia in the pathogenesis of hypertension and Alzheimer's Disease
Authors: Forero Kathleen , Messer William S , Aboualaiwi Wissam
Published: December 2022

Background

Primary cilia are microtubule‐based organelles, extending from the surface of cells to sense extracellular signaling cues. We demonstrated that the inability of endothelial cilia to sense and transmit fluid‐shear stress can lead to nitric oxide (NO) deficiency and cause vascular HTN. HTN can cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment, contributing to the progression of AD. It is well documented that decreased biosynthesis of NO contributes to cerebral amyloid angiopathy in AD patients through increased deposition of Aβ. Disruption of the cholinergic neurotransmitter pathway, which is important for cognition, memory and learning abilities has been reported in AD patients. However, the connection between cilia and mAChR signaling in the brain has never been investigated. We propose a bold idea to look at the pathophysiological roles of cerebrovascular ciliary receptors in BP and AD.

Method

Immunofluorescence of human brain endothelial cells (HBECs) were employed to study AChM3R localization and its downstream effectors. Cilia length and function (eNOS activation) studies were carried out to examine if mAChRs activation would enhance cilia structure and function. siRNA‐mediated knockdown of Tulp‐3 was performed to block AChM3R trafficking to primary cilia and study its activity. HBECs were exposed to synthetic Aβ to study their effect on cilia structure and ciliogenesis. Vascular‐specific cilia and AChM3R knockout mice were generated to study blood pressure and AD manifestations.

Result

We discovered that AChM3R, PIP2, and eNOS localize to primary cilia. mAChR‐specific activation (CDD‐0102A) increases cilia length in HBECs and cilia formation in cilialess Tg737 cells and was also associated with an increase in eNOS activity. Exposure to 2.5 μM human Aβ42 resulted in significant reduction in primary cilia length and ciliation percentage. RNAi‐mediated knockdown of Tulp3 caused a significant decrease in AChM3R trafficking to the cilia, associated with altered activity, suggesting that ciliary AChM3R localization is important for its activity. Vascular‐specific AChM3R and Tg737 KO mice developed high BP. Studies to examine cognitive function in our animal models are underway.

Conclusion

Primary cilia play an important sensory role by hosting proteins and signaling molecules important for the regulation of blood pressure and cognitive function.
Integrative single‐nucleus RNAseq analysis identifies cell‐type‐specific expression perturbations in progressive supranuclear palsy
Authors: Min Yuhao , Wang Xue , İş Özkan , Patel Tulsi , Reddy Joseph S. , Nguyen Thuy , Chalk Jessica L , Tutor‐New Frederick Q , Crook Julia E. , Carrasquillo Minerva M. , Dickson Dennis W. , Zhang Ke , Allen Mariet , Ertekin‐Taner Nilufer
Published: December 2022

Background

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by cell‐type‐specific tau lesions in neurons and glia. Using bulk brain RNAseq, we previously identified PSP‐associated genes and co‐expression networks that are enriched with cell‐type marker genes. We extended our work to identify cell‐type‐specific expression perturbations in PSP using a systems approach and in vivo validations in a model system.

Method

Single‐nucleus RNAseq (snRNAseq) was performed using 33 frozen brain temporal cortex (TCX) samples from PSP and control brains. After quality control (QC), integration, and clustering of nuclei, each cluster was annotated for its cell type. We identified differentially expressed genes (DEG) in PSP and further investigated them using an independent bulk RNAseq dataset comprising 408 PSP and control TCX samples for replication and assessing co‐expression patterns. Top DEGs were identified and then validated using external bulk RNAseq datasets from a tau transgenic mouse model. Further, the ability of the validated DEGs to rescue tau‐mediated cellular toxicity was evaluated in a tau transgenic Drosophila model.

Result

After QC, 30 clusters comprised of 27,284 nuclei were obtained, encompassing two neuronal and six glial cell types. DEGs of each cluster revealed cell‐type‐specific PSP associations. Notably, many of the up‐regulated DEGs in the astroglial clusters were members of the bulk RNAseq co‐expression modules that were also up‐regulated in PSP and enriched with astrocytic markers. There were also consistent findings for the up‐regulated DEGs in the endothelial and microglial clusters, and for down‐regulated DEGs in the oligodendroglial clusters. Subsequently, we prioritized 240 DEGs with congruent cell‐type‐specific perturbations in snRNAseq and bulk RNAseq and validated 29 of those using transgenic mouse model data. Lastly, a significant number of the up‐regulated glial genes, when knocked down in a tau transgenic Drosophila model, led to reduced tau‐mediated cellular toxicity, suggesting novel potential therapeutic avenues.

Conclusion

PSP brains demonstrated robust cell‐type‐specific gene expression perturbations in the glial cells populations that were validated across different datasets. Importantly, inhibiting the up‐regulated expression perturbations rescued tau‐mediated toxicity in a Drosophila model. Our findings highlight the cell‐type‐specific transcriptome changes in PSP and provide potential therapeutic options for primary tauopathies.
Absence of Apolipoprotein E Exacerbates Prion Pathology and Promote Microglial Mediated Neurodegeneration
Authors: Lizińczyk Anita M , Pankiewicz Joanna E. , Franco Leor A. , Diaz Jenny R , Ariza Mitchell Marta , Sadowski Martin J.
Published: December 2022

Background

Both Alzheimer’s disease and prionoses are neurogenerative disorders, which involve misfolded protein deposition and transition of homeostatic microglia to their neurodegenerative phenotype. In prionoses, accumulation of toxic PrPSc protein constitutes the culprit of pathogenesis. Neurodegenerative phenotype microglia (MGnD) appear early in the course of disease and play opposing roles in PrPSc mediated neurodegeneration. Whilst clearance of PrPSc has a disease‐limiting effect, MGnD‐driven neuroinflammation is deleterious to neurons. Apolipoprotein (apo) E is a pleiotropic protein, which controls MGnD phagocytic and inflammatory characteristics. Despite prominent role of microglia in prionoses, involvement of apoE in their pathogenesis has not been established.

Method

Wild type (WT) and Apoe‐/‐
mice, both on the B6 background, were inoculated with 22L mouse adapted scrapie strain or normal brain homogenate. Neuropathological and biochemical analyses were performed 15 and 23 weeks post inoculation (WPI) on asymptomatic and overly symptomatic animals, respectively. NanoStringTM analysis of microglia and astrocytic transcriptomic markers was performed at 23WPI.

Result

Prion infection of WT mice upregulates total brain apoE level and effects cell‐type shift in the apoE expression, downregulating astrocytic apoE while increasing microglial apoE 24‐folds. 22L
Apoe‐/‐
mice have significantly shorter disease incubation period, higher load of spongiform changes, and increased total brain PrP and PrPSc levels compared to 22LWT mice. In 22L
Apoe
‐/‐ mice astro and micro gliosis appears earlier and is more robust compared to 22LWT mice. Transcriptomic analysis shows significantly higher level of PAN and A1, but not A2 astrocytic markers and MGnD markers in 22L
Apoe
‐/‐ mice compared to 22LWT animals. Microglia in 22L
Apoe
‐/‐ mice feature impaired neuronal phagocytosis and produce increased level of pro‐inflammatory interleukins and cytokines. 22L
Apoe
‐/‐ mice show higher neuronal loss and greater tempo of neuronal degeneration than 22LWT mice.

Conclusion

Our results indicate the net effect of apoE in prion pathogenesis is protective. ApoE facilitates clearance of PrPSc and dying neurons by microglia, which becomes ineffective in the absence of apoE. Remnants of disintegrating neurons promote MGnD phenotype transition and inflammatory cascade propagating the vicious cycle of neuronal death and neuroinflammation. Our data also indicate homeostatic microglia transit to the MGnD even if they do not express apoE.
Patient and Care Partner Ratings of Communication Participation in Frontotemporal Dementia
Authors: Utianski Rene L , Clark Heather M , Martin Peter R , Stierwalt Julie A.G. , Duffy Joseph R , Botha Hugo , Ali Farwa , Josephs Keith A
Published: December 2022

Prior studies have shown communication‐related participation restrictions in patients with degenerative disease do not always match clinician judgment of symptom severity. Relatedly, there is a growing body of literature documenting discrepancies between patients with dementia and care partner perception of participation restrictions. However, it is not known how care partner perceptions of communication participation restrictions match or diverge from the patient's experience, which was the topic of this study.

Toward that end, 28 patients with apraxia of speech and/or dysarthria associated with primary progressive apraxia of speech, nonfluent/agrammatic primary progressive aphasia, or progressive supranuclear palsy, all types of frontotemporal dementia, were seen for speech‐language examinations. The patients and their care partners were asked to independently complete the Communication Participation Item Bank (CPIB), short form, which is a 10‐question survey about communication in different contexts; higher scores reflect less interference from their condition on communication. Care partners were instructed to complete the form with their perception of the patient's restrictions. The total CPIB score (maximum 30) and difference scores were calculated and visualized.

The data (Figure) suggest mismatches exist in care partner and patient ratings of communication participation restrictions. Of 28 patients, only 1 pair had identical scores, each rating severe interference in all communication contexts. 57% of patients rated communication as less impacted (higher scores) compared to their family member, leaving 39% of family members rating communication as less impacted than their loved one's perception. This study lays the foundation for future research to include patient and care partner ratings when examining the benefit of impairment‐based therapy, utilization of compensatory speech strategies, effectiveness of such strategies, and impact of other augmentative or alternative means of communication. The CPIB may be useful to document reduced psychosocial impact of disease and diminished burden and burnout on care partners with different intervention options. Future studies will explore possible differences between FTD phenotypes and, more specifically, whether 1) the motor speech disorder (MSD) disorder is primary or secondary to other motor impairment, 2) the nature or severity of the MSD, or 3) concomitant cognitive‐communication impairment predict the existence of and/or direction of a discrepancy.
Cerebrovascular reactivity is related to enlarged perivascular spaces in the basal ganglia among cognitively normal older adults
Authors: Libecap Timothy Justin , Bauer Christopher E. , Zachariou Valentinos , Raslau Flavius D , Gold Brian T.
Published: December 2022

Background

Cerebral small vessel disease (cSVD) is characterized by several in‐vivo neuroimaging biomarkers including enlarged perivascular spaces (ePVS). PVS are fluid‐filled spaces that play a role in the glymphatic system’s removal of brain waste. Arterial pulsatility drives waste removal through the PVS. Thus, arterial stiffness, a common feature of brain aging, may lead to waste accumulation and perivascular space enlargement.

Method

We explored the relationship between arterial stiffness and ePVS counts in 80 cognitively normal older adults ranging in age from 60‐85. Participants were scanned on a 3T Siemens Prisma scanner with a 64‐channel head coil. Arterial stiffness was assessed using cerebrovascular reactivity (CVR), a measure of the ability of cerebrovasculature to dilate in response to hypoxia. Blood‐oxygen‐level‐dependent contrast imaging (BOLD) functional magnetic resonance imaging (fMRI) was used in conjunction with blocked administration of hypercapnic gas. CVR was computed in specific regions by dividing change in BOLD signal by change in end‐tidal CO2. All ePVS counts were performed on T1 MPRAGE and T2 FLAIR images while blinded to participant demographics and under the direction of a neuroradiologist. ePVS were defined as regions of hypointensity less than 3mm in diameter on T1 imaging and were distinguished from mimics by absence of T2 FLAIR hyperintensity. ePVS were individually and manually counted in a single, representative slice in the axial plane of the basal ganglia (BGePVS), centrum semiovale, hippocampus, and midbrain.

Result

Regression analyses controlling for age, sex, intracranial volume, and education demonstrated a significant, negative relationship between cross‐sectional whole brain CVR and BGePVS (β =‐0.338, P = 0.003). Moreover, CVR in the left basal ganglia was negatively related to BGePVS in the left basal ganglia (β = ‐0.401, P < 0.001), and CVR in the right basal ganglia was negatively related to BGePVS in the right basal ganglia (β = ‐0.444, P < 0.001).

Conclusion

Our findings indicate a regional relationship between lower CVR and BGePVS burden, suggesting BGePVS are related to arterial stiffness. Longitudinal studies are required to address causality. Future work should compare other potential mechanisms of perivascular space enlargement to strengthen the hypothesis that arterial stiffness leads to ePVS.
Cultural adaptation and validation of the social functioning in dementia scale (SF‐DEM) in Taiwanese patients with dementia
Authors: Yu Ruan‐Ching , Sommerlad Andrew , Mukadam Naaheed , Livingston Gill
Published: December 2022

Background

The social functioning in dementia scale (SF‐DEM) is a 20‐item interviewer‐administered questionnaire, with patient‐ and carer‐rated versions. It was the first test designed to measure social function in people with dementia. It has not been validated in people with dementia in a Taiwanese population. We aimed to culturally adapt then validate the SF‐DEM in Taiwan and explore correlates of social functioning.

Method

We culturally adapted the SF‐DEM for Taiwan (T‐SF‐DEM) according to guidelines and tested it with people with clinically diagnosed dementia and their caregivers in Northern Taiwan We used descriptive and correlation analysis to explore how scores relate to the Clinical Dementia Rating (CDR), Addenbrooke’s cognitive examination III (ACE‐III) and Quality of Life in Alzheimer’s Disease (QoL‐AD).

Result

We recruited 12 people aged 45 to 100 with dementia (5 Alzheimer’s disease, 4 Vascular dementia, 1 Parkinson’s disease dementia, and 2 mixed. All patients and 11/12 (92%) of carers completed the SF‐Dem. Nine participants (75%) scored 0.5 on CDR and three (25%) scored 1. The mean ACE‐III score was 64.4 (standard deviation (SD) 11.9). The mean scores of patients and their carers for the sub‐domains of “spending time with other people (max 21 points)” were 3.3 (3.1) and 4.9 (3.4), for “communicating with other people (max 18)” were 5.7 (4.0) and 5.4 (3.8), for “sensitivity to other people (max 12)” were 10.9 (1.8) and 8.7 (2.6). The correlation between carer‐ and patient‐ratings was low (r = 0.33). There was a moderate correlation of the carer‐rated SF‐DEM with ACE (r = 0.66) and carer‐rated quality of life (r = 0.44). Seventy‐five percent of patients stated that they did not want to change their social life, while 100% of the carers stated they would like the patients’ social life to change.

Conclusion

The T‐SF‐DEM is an acceptable test for measuring social function in Taiwanese populations in memory clinic settings. Patients scored low on social contact as they were isolated due to the pandemic. We will test SF‐DEM in more patients and report the results.
Mild behavioral impairment is associated with plasma p‐tau181 in a dementia‐free population
Authors: Ismail Zahinoor , Ghahremani Maryam , Chen Hung‐Yu , Wang Meng , Zetterberg Henrik , Smith Eric E.
Published: December 2022

Background

Mild behavioral impairment (MBI) is a validated neurobehavioral syndrome describing emergent and persistent neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. In cognitively normal older adults MBI is associated with positron emission tomography and cerebrospinal fluid measured amyloid‐β and tau, the characteristic hallmarks of Alzheimer’s disease (AD). Plasma p‐tau181 is a blood‐based biomarker recently identified as an accessible alternative for in‐vivo detection of AD pathologies. So far, no study has explored plasma p‐tau181 in MBI. Here, we investigated the cross‐sectional and longitudinal associations of MBI with plasma p‐tau181 in dementia‐free older adults, and the associations of MBI with risk of AD.

Method

The sample included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who were cognitively unimpaired (CU) or had mild cognitive impairment (MCI). MBI status was determined using NPS total score at baseline and year‐one. NPS scores were derived from the Neuropsychiatric Inventory and categorized as persistent NPS (i.e., MBI, score>0 at both visits); transient/impersistent NPS (score>0 at only one visit); and no NPS (score = 0 at both visits). Cross‐sectionally, linear regression models were fitted with p‐tau181 as dependent variable and NPS profile as independent variable. Longitudinally, Cox proportional hazards models examined associations between NPS profile and incident dementia. Multilevel linear mixed effect (MLME) models assessed the associations between NPS status, categorized as within‐person NPS variability (impersistent NPS, not consistent with MBI) and between‐person NPS burden (persistent NPS, consistent with MBI), and p‐tau181 across four years.

Result

The final sample consisted of 571 dementia‐free participants (age 72.2, 46.8% females). Compared to no NPS, participants with persistent NPS but not transient NPS had higher baseline plasma ptau‐181 levels. Longitudinally, persistent NPS were associated with 3.42 times greater risk for dementia compared to no NPS. MLME analyses on annual measures of NPS and p‐tau181 over four years demonstrated that only the between‐person NPS measure was associated with higher p‐tau181 levels.

Conclusion

These findings extend the evidence base that MBI is a clinically relevant syndrome associated with the AD pathophysiological process. Incorporating MBI into clinical screening may help to identify those with preclinical or prodromal AD.
The effect of socioeconomic status on cognitive and socioemotional processes in Latin American older adults
Authors: Migeot Joaquín , Calivar Mariela , Granchetti Hugo , Ibáñez Agustin , Fittipaldi Sol
Published: December 2022

Background

Socioeconomic status (SES) negatively impacts cognitive and executive functioning in older adults, yet its effects on socioemotional abilities have not been studied in this population. Also, evidence on neurocognitive processes associated with aging primary comes from Western, educated, industrialized, rich, and democratic (WEIRD) populations, hindering the generalization of findings to those from upper‐middle‐ and low‐middle‐income countries, such as Latin America.

Method

Here, we compared the performance of low‐ and high‐SES older adults from Argentina in cognitive state, executive functions, social cognition (emotion recognition and theory of mind), and counter‐empathic social emotions (envy and Schadenfreude; displeasure at others’ fortune and pleasure at others’ misfortune, respectively). Subsequently, we developed a path analysis to test the directionality of the relationship among those variables in a theoretically plausible model and tested the main paths via multiple regression analyses.

Result

Relative to the high‐SES group, low‐SES older adults showed markedly poorer performance on all assessed domains. Convergent evidence from covariance, multiple regression, and path analyses suggested that SES impact on socioemotional processes was not primary but mediated by cognitive and executive decline.

Conclusion

These findings offer the first characterization of SES impacts on cognitive and socioemotional processes in non‐WEIRD population and have relevant equity‐related implications for brain health.
Feasibility and reliability of telephone‐based cognitive assessment in middle‐aged and older adults in the Wisconsin Alzheimer’s Disease Research Center
Authors: Thor Yer , Basche Kristin E , Wahoske Michelle L , Spalitta Alice , Chin Nathaniel A. , Gleason Carey E. , Clark Lindsay R.
Published: December 2022

Background

Use of telephone‐based cognitive assessments became more widespread during the COVID‐19 pandemic. The National Alzheimer’s Coordinating Center (NACC) developed the telephone‐based cognitive battery (T‐Cog) to ensure continued data collection and participant retention. The objective of this study was to (1) assess the feasibility and reliability of T‐Cog data collected during the pandemic, (2) evaluate these data in the context of prior in‐person data and (3) inform future use of remote data collection.

Method

The Wisconsin ADRC Clinical Core staff administered T‐Cog batteries to participants with normal cognition, mild cognitive impairment (MCI), or dementia (n = 380, mean age = 68.7±8.9, 66.1% female, 78.4% white, mean education = 16.2±2.48) (Table 1). Examiners rated the validity of the testing session and noted reasons for an invalid session. Reliability was assessed by comparing individual neuropsychological test performances from the T‐Cog to the most recent in‐person evaluation using intraclass correlation coefficients (ICC). Chi‐square was used to test if research diagnoses (normal cognition, MCI, dementia) varied by modality (T‐Cog, in‐person).

Results

Most T‐Cog sessions were rated as valid by examiners (87.8%). The most common reasons for questionable or not valid session included hearing impairments, distractions, and interruptions (Figure 1). Measures of verbal fluency (Animal Naming (ICC = 0.69), F+L Fluency (ICC = 0.73)), list‐learning and memory (RAVLT Trials 1–5 (ICC = 0.75), RAVLT Long Delay Recall (ICC = 0.70), RAVLT Recognition (ICC = 0.71)), and story memory (Craft Story‐Immediate (ICC = 0.65), Craft Story‐Delayed (ICC = 0.73)) showed moderate to excellent reliability and were significant (p<0.01), suggesting good agreement between T‐Cog and in‐person assessments (Table 2). Measures of attention (Digit Span Forward (ICC = 0.66), Digit Span Backward (ICC = 0.15)) varied from moderately reliable to not reliable, respectively. Lastly, research diagnoses did not differ by testing modality.

Conclusion

These results suggest T‐Cog assessments are feasible for participants who cannot complete in‐person visits, given adequate hearing and limited distractions and interruptions to ensure test validity. Preliminary comparisons of T‐Cog vs in‐person performances suggest good reliability for verbal fluency, story memory, and list‐learning measures. Although remote assessments can expand access and diversify the population involved in AD research, identifying assessments that are both feasible and reliable across varied administrations will be essential to track longitudinal change in cognitive status.
Susceptibility of aged pericytes to Aβ1‐42 oligomers
Authors: Randall Ryleigh B. , Bauman Allison J. , Bobinger Hanna V. , Saiyasit Napatsorn , Nelson Amy R.
Published: December 2022

Background

Aging is associated with increased incidence of Alzheimer’s disease, blood brain barrier breakdown, and increased cellular senescence (Saez‐Atienzar et. al, 2020). Senescence is the permanent arrest of the proliferative state of the cell and is initiated as a result of aging and cellular stress (Martínez‐Cué et.al, 2020). Senescent cells induce production of proinflammatory cytokines. In the brain, chronic inflammation leads to synapse damage and cognitive decline (Saez‐Atienzar et. al, 2020). The objective of this study is to examine the impact of cellular senescence on brain vascular pericytes, which contribute to the regulation of cerebral blood flow.

Method

For this study, both in vitro as well as in vivo experiments were performed. To induce senescence by oxidative stress in vitro in a culture of mouse brain vascular pericytes, 100 uM of hydrogen peroxide was added to culture flasks. Senescence was confirmed in the treated cells via staining for β‐galactosidase, a known biomarker of senescent cells. The next steps for the in vitro aspects of this study include performing western blotting on senescent pericytes to determine if there is a differential expression of pericyte p75 neurotrophin receptor (p75NTR), which has a potential role in the impaired hemodynamic response and cell death in pericytes. Finally, cranial window procedures were performed on 18‐month‐old C57BL/6 mice followed by imaging the live brain tissue with a multiphoton microscope. While imaging, artificial cerebral spinal fluid (control animals) or 72 nM amyloid‐beta (Aβ)1‐42 oligomers were topically delivered to the brain surface to determine if Aβ1‐42 oligomers cause a significant reduction in erythrocyte flow through pericyte covered capillaries.

Result

Preliminary data from the β‐galactosidase staining suggest that the hydrogen peroxide is an effective method for inducing senescence in mouse brain vascular pericytes. We have observed a decreased growth rate in cells treated with the hydrogen peroxide, further suggesting senescence in these cells.

Conclusion

These findings characterize the impact of Aβ on pericyte contractility and could illuminate the role of senescence and aging on impaired hemodynamic responses because of dysfunctional pericytes.
Chronic FK506 treatment reduces amyloid β and tau levels in the hippocampus and cortex of 3xTg‐AD mice
Authors: Fracassi Anna , Marcatti Michela , Saieva Salvatore , Taglialatela Giulio
Published: December 2022

Background

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. While major histopathological hallmarks of AD are amyloid‐β (Aβ) plaques and neurofibrillary tau tangles, soluble oligomeric forms of Aβ and tau (TauO) have been identified as the most neurotoxic species involved in synaptic degeneration. Previous studies associate alterations of the phosphatase calcineurin (CaN) to AβO‐driven toxicity. We previously have shown that CaN mediates both the neurotoxic and cognitive effects of AβO and elevated CaN levels have been also shown in AD patients, suggesting a central role of CaN in AD onset and/or clinical progression. Our previous studies in mouse models demonstrated that an acute treatment with the CaN inhibitor FK506/Tacrolimus in Tg2576 acutely injected intracerebroventricularly with AβO restores memory function in these cognitively impaired animals. Moreover, we reported absence of AD in aging human chronically treated with KF506 following solid organ transplant. To deeper investigate the involvement of CaN in AD onset and progression, we used a 3xTgAD mouse model presenting both Aβ and Tau aggregates.

Method

7 month‐old 3xTg‐AD mice were chronically treated for two weeks with intraperitoneal administration of either FK506 (1mg/kg) or PBS. Using immunofluorescence and western blot analyses we analyzed the levels of CaN, total Tau and Aβ in hippocampal (dentate gyrus‐DG, CA1 and CA3) and cortical areas (frontal and parietal‐occipital cortex) in our experimental groups.

Result

We found significantly decreased levels of CaN in DG, CA1 and CA3 and cortical areas in FK506 treated 3xTg‐AD mice as compared to 3xTg‐AD mice injected with PBS. Furthermore, performing double staining for Aβ and total Tau, FK506 treated mice displayed significant lower levels of Aβ and Tau in all the considered areas as compared to PBS‐treated 3xTg‐AD mice. These data suggest that the treatment with FK506 might trigger some mechanisms involved in the elimination of Tau and Aβ, i.e. autophagy.

Conclusion

Our data confirm the role of CaN as a key player in AD. The reduced key AD pathology following CaN inhibition with FK506 suggests the use of an FDA approved drug as a potential treatment with rapid clinical translation to slow the progression of the disease.
Next Generation Sequencing analysis of late‐onset dementia patients with a strong family history
Authors: Gómez‐Tortosa Estrella , Agüero Pablo , Sainz María José , Pérez‐Pérez Julián
Published: December 2022

Background

Next‐generation sequencing (NGS) techniques allow for efficient screening of potentially pathogenic variants by using gene panels that target the genes known to underlie neurodegenerative dementias. Most NGS studies are focused on cases with early‐onset disease, which have a higher genetic burden. The objective of this study is to identify known and/or novel rare variants in major candidate genes associated with neurodegenerative dementias in cases with a strong family history, including patients with late‐onset disease.

Method

We studied 53 patients (25 early‐ and 28 late‐onset) with a strong family history of dementia (Goldman scale 1 and 2) and phenotypes including dementia of the Alzheimer type (DAT), frontotemporal variants (FTD) and Lewy body type dementia. Presence of the C9Orf72 hexanucleotide repeat expansion had been ruled out and all cases had plasma progranulin levels within the normal range. The NGS panel included 20 genes. Variants identified were reviewed in genomic databases and analyzed for potential pathogenicity using prediction programs. Segregation was evaluated in available siblings.

Result

Potentially pathogenic mutations (CADD >20 and/or M‐CAP > 0.025) were found in 20 cases (38%, 11 early‐onset and 9 late‐onset), with two cases carrying mutations in two different genes. We detected known pathogenic mutations in two cases with the SQSTM1 P392L variant, manifesting as bv‐FTD and Paget disease. Six cases had non‐described variants in the PSEN1, ADAM10, SORL1, UBQLN2, and TIROBP genes that were likely disease‐related, as further supported by segregation patterns. We also found rare, potentially pathogenic variants in the SORL1, SQSTM1, and FUS genes in four cases. Finally, ten cases carried variants of unknown‐impact in the following genes: MAPT, CSF1R, ADAM10, SORL1, and SERPINI1. In the late‐onset cases, frontotemporal phenotypes were more likely to have positive results and the potentially pathogenic variants were found in the PSEN1, ADAM10, SQSTM1, FUS, and CSF1R genes.

Conclusion

It is worthwhile to screen for the genetic causes of the disease in cases with late‐onset dementia if there is a strong family history. Positive results are more likely obtained in frontotemporal phenotypes.
SINGLE AND COMBINED EFFECTS OF 5GHZ FREQUENCY WAVES AND COMPUTED TOMOGRAPHY(CT) SCAN DOSES ON WHOLE BLOOD PARAMETRES, MEMORY AND P53 GENE EXPRESSION IN RATS
Authors: Obajuluwa Adejoke Olukayode , Danlami Amina , Onwuka Chidiogo Chukwunweike , Bolarinwa Rahman Ayodele , Lech James , Obajuluwa Tiwalola Madoc , Anish Abel
Published: December 2022

Background

Exponential increase has emerged globally in the use of non‐ionizing and ionizing radio‐frequency electromagnetic fields(Rf‐emfs) for a wide range of applications, daily activities, communication, diagnostics , therapeutics to mention but a few. However, a significant public concern is how these technologies interacts and affects the biota as electromagnetic field (EMF) emissions is linked to dysregulation of genes involved in neurotransmission,oxidative stress and normal cellular function.

Methods

Standard methods (y‐maze, novel object recognition tests, automated hematology analyzer, PCR etc), were used to study how the combination of EM waves from 5Ghz radio and CT irradiation affects whole blood parameters, neurobehavioural profiles (memory and cognition), DNA fragmentation and p53 gene expression in Wistar rats which were grouped into five namely: I‐Negative control, II‐sham, III‐5Ghz only , IV‐ 5Ghz+CT, V‐CT only for fourteen days. Genomic DNA was isolated from rats’ cerebral cortex while target gene and internal control primers (GAPDH) were synthesized for p53 gene exons expression and electrophoresed on a 2.5% agarose gel.

Results

We found that CT irradiation had higher modulatory effects on platelets, white blood cell counts and memory impairments compared to 5GHz only group. However, there was gross DNA damage and complete loss of p53 (exons 5‐7) gene expression profiles in the 5GHz while the CT irradiated rats expressed mutant p53 gene. The effect of CT irradiation in pre‐exposed 5GHz rats revealed mutant p53(exons 5‐7), elevated memory and cognition impairments amongst others .

Conclusion

Deleterious single effects of 5GHz was observed in p53 gene expression profiles and cognition with an interferential interaction in its combination with CT irradiation leading to mutant p53 gene expression . The impaired neurobehavioural and p53 gene profiles as a result of the single and combined 5GHz and CT exposure predicts functional radiation waves emission effects, changes in resultant protein and dysregulated cellular functions.