bluuebunny/crossref_metadata_2025 huggingface dataset:
The prevalence of unrecognized cognitive impairment in geriatric surgical patients: A systematic review and meta‐analysis
Authors: Kapoor Paras , Saripella Aparna , Chen Lina , Riazi Sheila , Wong Jean , Englesakis Marina , Nagappa Mahesh , Chung Frances
Published: December 2021

Background

Pre‐existing cognitive impairment is emerging as a predictor of poor postoperative outcomes in older surgical patients (Guenther, 2020). Due to a substantial under‐diagnosis of cognitive impairment in the elderly, the prevalence of undiagnosed cognitive impairment has not been well defined in those undergoing surgery (Elman, 2018). The objective of this systematic review and meta‐analysis is to determine the pooled prevalence of unrecognized cognitive impairment in the elderly undergoing elective noncardiac surgery.

Method

An expert librarian conducted the literature search, which included MEDLINE (Ovid), PubMed (non‐MEDLINE records only), Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsycINFO, and Emcare Nursing for relevant articles from 1946 to April 2021. Inclusion criteria were (1) patients ≥ 60 years old undergoing elective non‐cardiac surgeries; (2) preoperative cognitive impairment assessed by validated cognitive screening tests; (3) published in English language. Descriptive analysis was conducted for the cognitive impairment group. Data were extracted from each study and prevalence of cognitive impairment with 95% confidence interval (CI) was calculated for each study. We used the random effect model to calculate the pooled prevalence value with 95% CI. Comprehensive meta‐analysis software was used for statistical analysis (Borenstein, 2013).

Result

Of 8,895 citations, 20 studies were included consisting of 4,159 patients undergoing a variety of elective non‐cardiac surgeries. All but one study were prospective cohort studies, with the exception being a cross‐sectional study. The mean age among patients with unrecognized cognitive impairment was 73.1 ± 7.2 years, and 43.6% were male. The pooled prevalence of cognitive impairment was 40.2% (95% CI: 31.0%, 50.1%; P=0.005; predictive interval: ‐1.47 to 2.27 (Table 1). The forest plot displays non‐overlapping CI's, indicating high heterogeneity within the data (I2: 97%). Influential analysis of any study showed that removal of each study did not significantly alter the pooled prevalence result. Meta‐regression analysis based on age, gender, and body mass index (BMI) did not change the final inference of our results.

Conclusion

The prevalence of unrecognized cognitive impairment is very high at 40.2% in geriatric patients undergoing elective non‐cardiac surgery.
Multivariate computational linguistic analysis for early detection of cognitive impairment
Authors: Lee Evan T. , Ebinu Julius O.
Published: December 2021

Background

The overarching goal of this study was to develop a novel computational linguistic algorithm that can be used to build a machine learning platform for recognizing changes in cognitive abilities during the progression of psychopathological disorders or predicting clinical prognosis following a brain injury or therapeutic interventions.

Method

The computational linguistic algorithm developed in this study evaluates lexical diversity, lexical complexity, and emotional tones in a quantitative manner. An existing algorithm that quantifies idea density was also included in this study. The initial proof‐of‐concept study was performed on various published books by well‐known authors, including Iris Murdoch who developed Alzheimer’s disease (AD) later in life. Ten interviews of patients with mild AD and ten interviews of healthy age‐matched individuals were evaluated. The transcript of each video was produced manually. Each transcript was analyzed using the computational linguistic algorithm for lexical diversity/complexity, emotional tones, and idea density. Quantitative linguistic values were compared between patients with mild AD and healthy age‐matched individuals.

Result

A computational linguistic analysis of various books resulted in findings that were consistent with the nature and subject of each book. Among all the computational linguistic variables evaluated in this study, the book written by Irish Murdoch after the onset of AD showed a decrease in the level of lexical complexity by 17.5%. Interestingly, a 20% decrease in the level of lexical complexity was also noted when video interviews of patients with mild AD were compared to normal age‐matched individuals. The video transcripts of AD patients showed a statistically significant increase in the levels of anger, fear, and sadness. We are currently conducting a study to compare computational linguistic variables in response to writing prompts between patients with mild AD and healthy age‐matched individuals. Preliminary results indicate that patients with AD show a similar decrease in the level of lexical complexity as well as quantifiable changes in emotional tones.

Conclusion

The computational linguistic algorithm developed in this study may lead to a machine learning approach or artificial intelligence platform to detect linguistic changes that may occur in the human cognitive state for both diagnosis and/or prognosis of mental health conditions.
Assessing the effect of modified Mediterranean‐ketogenic diet on mild cognitive impairment patients through plasma neuron‐derived exosomes
Authors: Kumar Ashish , Sharma Mitu , Singh Sangeeta , Su Yixin , Hsu Fang‐Chi , Craft Suzanne , Deep Gagan
Published: December 2021

Background

Recently, we compared the effect of a high‐fat and low‐carb Modified Mediterranean‐Ketogenic Diet (MMKD) and a low‐fat American Heart Association Diet (AHAD) on 11 cognitively normal (CN) and 9 with mild cognitive impairment (MCI) older adults as a suggestive preventative intervention for Alzheimer’s disease (AD). We reported the promising effect of the MMKD on MCI patients as it was well‐tolerated and associated with increased cerebrospinal fluid (CSF) Aβ1‐42, decreased tau, and increased cerebral perfusion. Here, we characterized the plasma neuron‐derived exosomes (NDE) to further understand the molecular mechanisms underlying the efficacy of the MMKD against MCI.

Method

The completed study consisted of a randomized crossover design in which participants (both CN and MCI) consumed either the MMKD or the control AHAD for six weeks. Total exosomes (TE) were isolated from plasma by precipitation method, and NDE were enriched using Biotin‐tagged CD171 antibody attached with streptavidin‐magnetic beads. The purity, concentration, and size of TE and NDE were assessed by flow cytometry, nanoparticle tracking, immunogold‐labeling, electron microscopy, and exosome antibody array. NDE was characterized for several AD and neurodegeneration‐related biomarkers, advanced glycation endproducts (AGEs), glutamate, glutamate receptors, and β‐hydroxybutyrate (BHB) by ELISA and colorimetric assays. NDE effect on NF‐kB activity in human monocytes was studied as a molecular surrogate for inflammation.

Result

We confirmed the size, shape, and purity of both TE and NDE by multiple methods. Importantly, the MMKD treatment strongly reduced the level of Aβ1‐42 (by 50%, p=0.001), p(181)Tau (by 17%), and neurofilament L (by 55%, p=0.03) in the MCI group, but not with AHAD. MMKD reduced the AGEs in both CN and MCI groups and strongly increased the glutamate level in NDEs from the MCI group (6 fold, p<0.001) but did not affect glutamate in CSF. The MMKD also modulated the expression of various glutamate receptors (GRIN1, GRIA1, GRIN2A, and GRIN2b). Interestingly, we detected BHB in NDEs, though no significant change was observed. MMKD inhibited the NF‐κB activity in monocytes suggesting a strong anti‐inflammatory effect.

Conclusion

NDE offers a promising peripheral measure to assess the efficacy and molecular mechanism of MMKD action against MCI.
Association between sleep health and cognitive reserve in older adults with cognitive concerns
Authors: Kerner Nancy , Espejo Kimberly , Bell Sophie A. , Pollina Julianna , Goldberg Terry E. , Devanand Davangere P
Published: December 2021

Background

We examined the association between sleep health consequences and perceived fatigability within the context of carrying out everyday activities in non‐demented older adults and investigated whether cognitive reserve (CR; individual differences in susceptibility to cognitive decline due to brain aging, pathology, or insult) moderated this relationship.

Method

This was a cross‐sectional study. We prospectively screened adults age 55‐90 years at a Memory Research Clinic. An IRB approved the study protocol, and informed consent was obtained. Patients with cognitive concerns underwent neurocognitive testing to determine cognitive status based on the ADNI criteria. Inclusion criteria: the ADNI criteria for cognitively normal or MCI. Exclusion criteria: 1) depression assessed with the Geriatric Depression Scale (GDS>5) and DSM‐5 criteria, 2) history of primary psychiatric illnesses, 3) medical conditions associated with fatigue, and 4) a history of obstructive sleep apnea diagnosed by a clinical sleep physician. Measures included the PROMIS Sleep‐related Impairment (SRI); the Neuro‐QOL Cognitive function (CogF) and Fatigue measure, which yields “fatigue symptom severity (Fat_Sx)” and “perceived fatigability (Fatiga)” subscales. CR was assessed with the CR Index questionnaire (CRIq). Linear regression models were fit to the fatigue outcomes and included the SRI, CR, and their interaction as predictors. If the interaction was significant, SRI slopes were assessed at CR=mean and mean ±1SD. All analyses were adjusted for age, sex, and education.

Result

There were 37 subjects in this study; mean age of 70.8 years (SD=9.3); 70.3% subjects were female; 86.5% white, 10.8% Hispanic, and 2.7% others. CR significantly moderated the relationship between SRI and perceived fatigability (F (1,32)=18.64, p=0.011). A higher SRI score was associated with a higher perceived fatigability severity with a low CR (CRIq mean‐1SD)=108.6; b(se)=.493(.089), p<0.001) and a mean CR (CRIq mean=128.0; b(se)=.274(.076); p=0.001), but not a high CR (CRIg mean+1SD=147.4; b(se)=0.1278; p=0.636). Moreover, higher perceived fatigability was associated with lower cognitive function (b(se)=‐.24 2(0.077), p=0.004), controlling for age, gender, and education.

Conclusion

Poorer cognitive function was significantly associated with greater fatigability within the context of managing everyday activities. Greater cognitive reserve may reduce the detrimental influence of poor sleep health on perceived fatigability in managing daily function during the preclinical stages of dementia.
Positive clinical outcomes in two phase 2a studies: ADAS‐COG in Alzheimer’s and MDS‐UPDRS in Parkinson’s patients plus markers of toxic cascade that leads to nerve cell death
Authors: Maccecchini Maria L. , Hernandez Priscilla , Liow Kore , Zetterberg Henrik , Chen Michael
Published: December 2021

Background

Overexpression of neurotoxic proteins drives dysregulation of axonal transport, inflammation, nerve cell death, and loss of function. By inhibiting translation of amyloid precursor protein, tau and alpha‐synuclein our drug has been shown in animal models to restore axonal transport, lower inflammation and protect nerve cells and to restore full function in 7 animal models ‐ Down Syndrome [Chen 2020], Alzheimer’s [Teich 2018], stroke [Turcato 2018], traumatic brain injury [Chesselet], Parkinson’s [Kuo 2019], frontotemporal dementia [Davies], and acute glaucoma [Sundstrom]. We showed safety in over 130 healthy and sick people [Maccecchini 2012].

Methods

We are conducting a 2‐part double‐blind, placebo‐controlled phase 2a study in 14 AD and 14 PD patients, collected blood, CSF, conducted safety evaluations and psychometric tests. The patients were treated for 25 days. At the end of the study again safety, psychometric tests, blood and CSF. The plasma and CSF samples are being analyzed for AD and PD specific biomarkers, markers of axonal transport, inflammation, neurodegeneration and synapse health. The second part of the study is enrolling an additional 40 patients with the same study design.

Results

In AD patients, we are reporting statistically significant improvements in a number of ADAS‐Cog variables: Number of Cancellations, Word Recall, Commands, Spoken Language, Remembering Test Instructions, and ADAS‐Cog 11. In PD patients, we also see statistically significant improvements in speed, coordination and motor function. The first step of the toxic cascade to have been measured is inflammation. Specific markers measured are: YKL40, sTREM2 and GFAP. The statistical significance holds whether the levels are compared within at 0 and at 25 days or between placebo treated and Posiphen treated at 25 days.

Conclusions

We showed that our drug improves cognition in AD and motor function in PD. The PD data is substantiated by the lowering of inflammatory markers. We are in the process of showing that by lowering more than one neurotoxic protein, our drug reverses the toxic cascade that leads to nerve cell death and loss of function. We still have a lot of markers to measure in CSF and plasma and expect to finish by July.
Overcoming social isolation: A dementia‐ friendly guide to adapt during a global pandemic
Authors: Tokarczuk Pam
Published: December 2021

Background

The pandemic left millions of families with the unsustainable burden of tending to their loved ones’ cognitive, emotional, physical and spiritual wellbeing. Without the tools, training or expertise, they simply cannot fulfill this responsibility on their own. Dementia care experts, despite the heavy regulations placed on them, offer these families their only true window of hope. Learn how to flip the script during these harrowing times. We will examine how care providers can help families overcome these devastating hardships by giving them and their loved ones the tools they need to stay connected.
Investigating the role of Synaptotagmin‐1 at ribbon synapses
Authors: Jamal Armaan , Markert Sebastian , Watanabe Shigeki
Published: December 2021

Background

Photoreceptors possess a specialized form of proteinaceous electron‐dense projection: the synaptic ribbon that exhibits graded neurotransmitter release. The molecular mechanism underlying graded release is unknown. Data suggests that synaptic vesicles at ribbon synapses undergo homotypic compound fusion where vesicles may only travel a short distance to the neighboring vesicles and fuse with each other around the ribbons1. Here we demonstrate that Synaptotagmin‐1 (Syt1) functions in compound fusion as it promotes full formation of the SNARE complex fusion machinery in response to calcium influx2. A better understanding of synaptic ribbon communication proteins may lead to novel drug targets to aid in therapeutic design

Method

Syt1 knock‐down (KD) was developed using a CRISPRi system in Danio rerio larvae (n=100) and incubated for 5 days. Flash‐and‐freeze electron microscopy was performed on the Syt1 KD line and controls (n=100) by stimulating and freezing the samples at time points 0, 3, 6, 9 and 15 milliseconds after exposure to light for 30 seconds. Samples were fixed in epoxy resin and viewed under TEM. Blind analysis using ImageJ was performed to identify the presence of any compound fusion.

Result

Mean compound fusion frequency was highest at the 6ms and 9ms time points in Danio rerio controls. At the 6ms timepoint, compound fusion was seen at the middle of the ribbon and at 9ms, compound fusion was seen closer to the base. Prevalence of compound fusion was significantly reduced at the 6ms and 9ms time points in the Syt1 KD compared to controls.

Conclusion

Syt1 is can mediate compound fusion on a millisecond timescale during exocytosis.

1. Matthews G, Sterling P. Evidence That Vesicles Undergo Compound Fusion on the Synaptic Ribbon. J Neurosci. 2008;28(21):5403‐5411. doi:10.1523/JNEUROSCI.0935‐08.2008

2. Chicka MC, Hui E, Liu H, Chapman ER. Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca2+. Nat Struct Mol Biol. 2008;15(8):827‐835. doi:10.1038/nsmb.1463
Characteristics of referrals to national assessment for eligibility into the Specialist Dementia Care Program (SDCP) in Australia
Authors: Atee Mustafa , Morris Thomas , Macfarlane Stephen , Cunningham Colm
Published: December 2021

Background

Dementia is a progressive neurodegenerative disease that is characterized by the presence of behaviors and psychological symptoms (BPSD), such as agitation and hallucinations. BPSD frequently have considerable negative social and clinical outcomes, such as inappropriate drug therapy, caregiver distress, institutionalization, and reduced quality of life. Thus, dementia requires significant care and support, particularly in the advanced stages. A new initiative funded by the Australian Government; the Specialist Dementia Care Programs (SDCPs) provide a person‐centered, multidisciplinary care within special accommodation units for people with severe dementia (up to 12 months) who cannot be cared for by mainstream aged care services. Eligibility assessments for SDCP’s placements are conducted by Dementia Support Australia (DSA) through its national Needs Based Assessment (NBA) program (Figure 1). This study describes the referral characteristics of the NBA program.

Methods

NBA referrals were deemed eligible for admission to SDCPs if they had: (1) behaviors primarily linked to dementia; (2) severe or very severe BPSD (e.g., aggression, severe agitation); and (3) proved intractable to adequate trials of treatment. Eligibility assessments were completed by a dedicated team of NBA consultants and psychogeriatricians. Demographic data of referrals were described for the period November 2019‐June 2021.

Results

Of the 471 referrals (age: 76.0 ± 8.3 y; 69.1% males) received during the specified period, 273 (58.0%) had an NBA assessment. Of these, two‐thirds (n = 178, 65.2%) were found eligible for SDCP placement. Eligible referrals (age: 74.6 ± 7.6 y; 72.3% males) had Alzheimer’s disease (n = 93, 52.2%), mixed dementia (n = 27, 15.2%), frontotemporal dementia (n = 17, 9.6%), vascular dementia (n = 14, 7.9%), and dementia with Lewy bodies (n = 8, 4.5%). Most eligible cases were referred from residential aged care homes (RACH; n = 70, 39.8%), hospitals (n = 55, 31.3%) and mental health services (n = 27, 15.3%) because of physical aggression (64.0%).

Conclusions

Typical characteristics of eligible NBA referrals to an SDSP placement (i.e., people with severe‐to‐very severe BPSD that require extensive support) included being male, aged on average 75 years old, resided in RACH, physically aggressive towards others, and had Alzheimer’s disease.
Diabetes is associated with poorer allocentric processing compared to non‐diabetic participants in the EPAD LCS cohort
Authors: Gregory Sarah
Published: December 2021

Background

Dementia and type 2 diabetes mellitus (T2D) are prevalent disorders in older adults, and increasingly T2D is recognized as a robust predictor of cognitive impairment, decline and dementia. Older adults with T2D experience global cognitive decline at a rate that is double those without T2D over a 5‐year period. With regard to specific cognitive domains, associations between T2D and pre‐diabetic levels of insulin resistance are most commonly reported with both episodic memory and decreased executive function, including verbal fluency, working memory, processing speed, cognitive flexibility, and cognitive control. Identification of those living with diabetes at risk for cognitive decline is critically important for early intervention.

Method

We used the EPAD LCS vIMI baseline dataset (n=1324, excluding participants with missing data). Our primary outcome measure was performance on the Four Mountains Test (4MT), a measure of allocentric processing. Diabetes was recorded in the medical history. Covariates were age, sex, years of education, family history, APOE status, pTau and Aβ1‐42. Our statistical analysis approach was linear regression.

Result

There were 90 participants with diabetes included in the sample. Their mean score on the 4MT was 8.32 (±2.32) correct (out of 15) compared to 9.24 (±2.60) for participants without diabetes. In uncorrected models, diabetes was significantly associated with worse 4MT total scores (β=‐0.92, p=0.001). This relationship remained significant in a fully adjusted model including sex, age, education, family history of dementia and APOE status (β=‐0.71, p=0.0017). There was no significant interaction between diabetes and APOE status. pTau was significantly higher in participants with diabetes compared to those without. Including pTau and Aβ1‐42 in the fully adjusted model further attenuated it but it remained significant (β: ‐0.62, p=0.02)

Conclusion

Individuals with diabetes performed worse on the 4MT compared to those without diabetes in the EPAD LCS v.IMI dataset. Novel cognitive tests, such as the 4MT, may be appropriate to identify early cognitive changes in this high‐risk group. Future research will investigate longitudinal associations between diabetes and 4MT performance over multiple visits.
APOE, TOMM40, and Sex Interactions on Neural Network Connectivity
Authors: Li Tianqi , Pappas Colleen , Le Scott T , Wang Qian , Klinedinst Brandon S , Larsen Brittany A , Pollpeter Amy , Lee Ling Yi , Lutz Michael W , Gottschalk William Kirby , Swerdlow Russell H , Nho Kwangsik , Willette Auriel A
Published: December 2021

Background

The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The Translocase of Outer Mitochondrial Membrane‐40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 (‘650) G vs. A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE.

Method

We examined 21 orthogonal neural networks among 8,222 middle‐aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 ‘650 genotypes, and if age and sex acted as moderators

Result

APOE ε4 was associated with less strength in multiple networks, while ‘650 G vs. A carriage was related to more language comprehension network strength. In APOE ε4 carriers, ‘650 G‐carriage led to less network strength with increasing age, while in non G‐carriers this was only seen in women but not men.

Conclusion

TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.
Deletion of the SPAG9 gene cause autosomal‐recessive intellectual disability
Authors: Acosta‐Baena Natalia , Tejada‐Moreno Johanna A. , García Alejandro Mejía , Caro María Antonieta , ‐Lanau Carlos Andrés Villegas , Bedoya‐Berrío Gabriel
Published: December 2021

Background

Intellectual disability (ID) is the limitation of intellectual functioning and adaptive behavior before 18 years of age. In a consanguineous family of 149 members, this disease is expressed in 9 individuals. Here, we report one branch of a family tree with three siblings, presenting severe ID, delayed speech development, cataracts, strabismus, gait disturbance, cerebellar syndrome, seizures in one of them, and eyelid ptosis in two. Brain magnetic resonance imaging (MRI) with hippocampal malrotation, brain atrophy and white matter hyperintensities in all cases. Thinning of the corpus callosum in two of them.

Method

We conducted whole exome sequencing analysis in nine subjects from one multigenerational family of Colombian origin. The study was carried out at the University of Antioquia,Colombia with the approval of the ethics committee. A medical, neurological, neuropsychological examination and brain MRI were performed in all cases.

Result

We identified a single nucleotide deletion in the SPAG9 gene, which codes for the JIP4 protein. The frameshift generates a premature stop codon (p.Tyr914Ter). The deletion is classified as pathogenic, according to the ACMG / AMP guidelines. The variant co‐segregated in the respective family as an autosomal recessive trait.

Conclusion

JIP 4 has two functions: As scaffold protein that potentiates the p38 MAPK signaling cascade under stress conditions and as dynein‐dynactin motor adapter for lysosomal retrograde flow, regulating the constitutive transport of lysosomes. Both functions could be associated in the disease mechanism. The absence of JIP 4 may be responsible for the disease in the family, altering neuronal homeostasis.
Ca2+/Calcineurin‐mediated release of exosomal miR‐23a regulates astrocyte‐neuron cross‐talk and protects against neuroinflammation and neurodegeneration
Authors: Bhattacharyya Pallabi , Biswas Subhas Chandra
Published: December 2021

Background

Astrocyte dysfunction and associated neuroinflammation is well implicated in various neurodegenerative disorders like Alzheimer’s (AD) and Parkinson’s diseases (PD). Importantly, Ca2+/Calcineurin signaling is reported to induce astrocyte dysfunction in AD (1) but very little is known regarding PD. So, our objective was to study the role of Ca2+/Calcineurin signaling in astrocyte‐neuron cross‐talk during PD‐related neuroinflammation which is unreported till date.

Method

1.Mammalian cell culture 2.Immunoblotting. 3.qRT‐PCR. 4.Exosome isolation. 5.Intracellular Ca2+ measurement. 6.Transfection (miRNA mimics). 7. 3’UTR cloning. 8.Luciferase assay.

Result

We treated human astrocytic 1321N1 cells with Rotenone, a neuro‐toxin known to induce PD‐associated neuroinflammation (2). At the dose of Rotenone which caused about 40% death in 24 hrs, simultaneous activation of the Ca2+‐dependent protein phosphatase Calcineurin and intracellular surge in the Ca2+ levels were also observed. Now, miR‐23a is an anti‐apoptotic miRNA and Calcineurin/NFAT‐mediated upregulation of miR‐23a has been reported in cardiac hypertrophy (3). Surprisingly, in our study, Rotenone caused a Calcineurin‐mediated decrease of intracellular miR‐23a levels in astrocytes. Now this decrease, we found, was due to a concomitant release of miR‐23a via exosomes. Can this anti‐apoptotic miR‐23a released by astrocytes protect the neurons? To answer this, we treated neuronal SH‐SY5Y cells with Rotenone and found that the pro‐apoptotic protein PUMA was upregulated although the miR‐23a levels remained unchanged. Interestingly, over‐expression of miR‐23a caused attenuation of the Rotenone‐mediated death in neurons. PUMA being a predicted target of miR‐23a, we cloned the 3’UTR of PUMA and subsequent luciferase assay revealed that indeed PUMA is a direct target of miR‐23a under our experimental conditions.

Conclusion

Our results suggest a novel mechanism by which Ca2+/Calcineurin‐mediated release of miR‐23a through exosomes regulates astrocyte‐neuron cross‐talk and plays a probable role in protection against neuroinflammation and neurodegeneration.

References:

1.Sompol P. et al. Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ‐Bearing Mice. J Neurosci. 2017 Jun 21;37(25):6132‐6148. 2.Javed, H., Azimullah, S., Abul Khair, S.B. et al. Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone. BMC Neurosci 17, 58 (2016). https://doi.org/10.1186/s12868‐016‐0293‐4. 3.Lin Z. et al. miR‐23a functions downstream of NFATc3 to regulate cardiac hypertrophy. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12103‐8.
Investigating changes in the proteostasis capabilities of iPSC‐neurons during development and in FTD using iPSC‐neurons with MAPT mutations
Authors: Lines Georgie , Arber Charles , Preza Elisavet , Leckey Claire Alexandra , Myeku Natura , Casey Jackie M. , Perkinton Michael , Wray Selina
Published: December 2021

Background

Mutations in microtubule‐associated protein tau (MAPT) gene are causative of Frontotemporal Dementia (FTD). Many of the features associated with the development of tau pathology, e.g high levels of tau phosphorylation, are also present in early development. iPSC‐neurons have gene expression signatures similar to fetal neurons, and iPSC‐neurons with MAPT mutations do not develop tau aggregates. We hypothesise that iPSC‐neurons are resistant to developing tau aggregates due to high activity levels of the proteostasis network during early development. To test this hypothesis, we investigated the levels of proteasome subunits in developing iPSC derived neurons and measured the proteasome activity of iPSC‐neurons throughout development. To test whether manipulation of proteostasis in iPSC‐neurons could lead to tau pathology we treated cells with a proteasome inhibitor, and measured changes in total and phosphorylated tau, proteasome subunits and autophagy regulators.

Methods

Human cortical neurons were derived from isogenic iPSCs with the following MAPT genotypes: WT, 10+16 monoallelic, 10+16 biallelic and 10+16/P301S biallelic. RNA and protein analysis of proteasome subunits was performed by qPCR and Western blot at during neuronal development (DIV 0, 10, 30 and 100) and after proteasome inhibition treatments.

Results

We show that proteasome activity decreases during the differentiation of iPSCs to cortical neurons, accompanied by a reduction in levels of the proteasome regulatory subunits Rpt6 and Rpn6. Proteasome inhibition in WT neurons does not lead to a significant change in total or phosphorylated tau levels but resulted in an increase in the autophagy associated protein BAG3, together with an induction of tau cleaved by caspase‐3 at Asp421.

Conclusion

Proteasome activity decreases during the differentiation of iPSCs into neurons, which may be due to a reduction in in proteasome regulators. Our results suggest that proteasome inhibition causes an increase in tau cleavage which may be preferentially cleared through the autophagy pathway. The ability of these ‘fetal‐like’ neurons to adapt and upregulate their protein clearance system may be enhanced compared to FTD brain tissue. In ongoing work we are investigating proteasome expression and activity in FTD post‐mortem tissue as well as the localisation and interactions of tau and the proteasome after proteasome inhibition treatments.
Identification of pharmacodynamics readouts through acute dosing of a small molecule inhibitor of tau self‐association in a tauopathy mouse model
Authors: Patel Dhruv R. , Sussman Chaya , Greco Mindy , Cheesman Edward H. , Lopez Patricia , Davidowitz Eliot J. , Moe James G.
Published: December 2021

Background

The accumulation of tau aggregates correlates with and facilitates disease progression in pure and mixed tauopathies such as Progressive Supranuclear Palsy and Alzheimer’s disease. However, a disease‐modifying‐therapeutic targeting tau aggregation has not yet shown success in the clinic. Our target approach is highly differentiated from other programs that are focused on inhibiting tau aggregation and all downstream cascades. We have selected and optimized small molecules capable of targeting tau self‐association (TSA), the first and rate‐limiting step in tau aggregation. We have demonstrated the efficacy of our lead TSA inhibitor in two mouse models of tauopathy (htau mice; tau‐P301L‐JNPL3 mice) in preventive and therapeutic studies. Treatment with the lead TSA inhibitor blocked tau self‐association and formation of large tau aggregates, reduced overall tau accumulation, and rescued impaired motor function in aged mice with pre‐existing tau aggregates. IND‐enabling studies for the lead TSA inhibitor are completing, and a FDA submission is planned for Q1 2022. In this study, we aim to identify acute measures of efficacy in aged homozygous female tau‐P301L‐JNPL3 mice that will be used to model Pharmacokinetics (PK)/Pharmacodynamics (PD) relationship of our TSA inhibitors.

Methods

Acute dose range‐finding (ADRF) study was performed using multiple routes of administration. C57BL/6 mice (n=30) were either administered vehicle or a single dose of a selected TSA inhibitor ranging from 2 to 200 mg/kg (n = 3 mice/gender/group). Biospecimens were collected at Cmax. PK studies in C57BL/6 mice will be performed with and without fasting to determine the food effects on bioavailability.

Results

Serum and brain homogenate samples from the ADRF study are being analyzed to evaluate TSA inhibitor concentrations by LC‐MS/MS. These results will be used to select the dose and route of administration for PK studies in 9 months‐old homozygous female JNPL3 mice. To determine the selective dose for PD evaluations, PK studies will be performed using three doses. Some of the PD measures that will be evaluated are tau self‐association, tau hyperphosphorylation, and motor behavior.

Conclusions

Understanding PK/PD relationship will be crucial for determining appropriate dosing and target engagement biomarkers in subsequent Phase‐1b studies.
Gelsolin Amyloidosis: aggregation propensities of wild and mutant peptides and their inhibition
Authors: Arias Carlos Quintero , Martic Sanela
Published: December 2021

Background

Gelsolin is an actin‐binding protein responsible for the remodeling of the actin cytoskeleton. Gelsolin Amyloidosis, the formation of misassembled protein into insoluble amyloid fibril aggregates, is the result of point mutations that promote aberrant proteolytic cleavage. Amyloidosis can be instigated and spread by existing amyloid fibrils through the process of seeding, where existing fibrils promote the formation of new fibrils. Gelsolin fragments are prone to aggregation and systematic deposition into organs including peripheral/cranial nerves, skin, eyes, and kidneys. The D187Y mutation has been identified to promote cleavage of Gelsolin, although studies have demonstrated the mutant’s elusive aggregation propensity.

Method

Mutant Gelsolin peptide aggregation was monitored and characterized in vitro using various spectroscopic methods, Thioflavin T (ThT), turbidity, and Dynamic Light Scattering (DLS). Transmission electron microscopy (TEM) allowed for the identification and visualization of β‐sheet formation within aggregates

Result

We reported that CFILDL‐containing peptides were prone to aggregation, which may be inhibited by using small molecules. Of note is the unique behaviour of peptide mutants with respect to their aggregation propensities pointing to their biological relevance. Preliminary results suggest that seeding may induce peptide aggregation

Conclusion

Since other neurodegenerative proteinopathies (Alzheimer’s & Parkinson’s) exhibit similar prion‐like mechanisms of seeding that initiate aggregation, understanding the fundamentals of seeding may expose potential therapeutic targets for preventing the progression of amyloidosis.

References 1) Ahmad, M., Esposto, J., Golec, C., Wu, C., & Martic‐Milne, S. (2021). Aggregation of gelsolin wild‐type and G167K/R, N184K, and D187N/Y mutant peptides and inhibition. Molecular and Cellular Biochemistry, 476, 2393–2408. https://doi.org/10.1007/s11010‐021‐04085‐6

2) Walker, L. C., Diamond, M. I., Duff, K. E., & Hyman, B. T. (2013). Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurology, 70, 304‐310. https://doi.org/10.1001/jamaneurol.2013.1453

3) Solomon, J. P., Page, L. J., Balch, W. E., & Kelly, J. W. (2012). Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention. Critical Reviews in Biochemistry and Molecular Biology, 47, 282–296. https://doi.org/10.3109/10409238.2012.661401

4) Ihne, S., Morbach, C., Sommer, C., Geier, A., Knop, S., & Störk, S. (2020). Amyloidosis‐the diagnosis and treatment of an underdiagnosed disease. Deutsches Ärzteblatt International, 117, 159–166. https://doi.org/10.3238/arztebl.2020.0159
Remote cognitive rehabilitation in patients post‐cerebrovascular accident: an experience report
Authors: Alves Larissa Scoralich , Dutra Letícia Silva , Santos Lucas Neves , Gonzaga Franciele Aparecida , Shigaeff Nadia
Published: December 2021

Background

Aiming to contribute to the reduction of cognitive impairment, as well as to improve the quality of life of patients affected by stroke, it was proposed to carry out a cognitive rehabilitation focused on attentional aspects (sustained, alternate, selective and divided attention). Due to the new Coronavirus pandemic and the need for social isolation, the rehabilitation was adapted to the remote model.

Methods

The rehabilitation was designed and carried out with six patients, coming from a public neurology outpatient service, who had suffered a stroke within a period of up to one year before the start of rehabilitation. Fifteen sessions of cognitive rehabilitation were carried out, lasting approximately 50 minutes, once a week, for four months. In all functions, the four types of attention were worked on. In addition, there were also unassisted activities performed by the patients after each session.

Results

The protocol was carried out by Psychology and Medicine students, who elaborated and adapted all activities to be performed by video call. The adaptations were made based on the knowledge and effectiveness of face‐to‐face rehabilitation for this population. Patients and family members collaborated in the activities, but the emergency adaptation to the remote model also had limitations, such as the withdrawal of some patients due to difficulty access or unstable internet connection. However, there were also positive results, such as the possibility of participation by people from other cities and people with mobility difficulties. This experience allowed students to develop skills in interacting with patients, as well as strategies to deal with the challenges of remote care. Thus, it was not necessary to interrupt the students´ education, moreover, the skills developed are important for the e‐health context, which is an increasingly present demand in today's world.

Conclusion

Remote cognitive rehabilitation is a possibility for patients who have suffered cognitive impairment due to stroke. Despite the difficulties arising from the pandemic, it was an important experience, with significant value for academic training, which stimulated the skills needed to care for patients, in addition to creativity and adaptation in the face of adversity.
The Role of PKR as a Potential Target for Treating Systemic Inflammation Triggered Neuroinflammation, Tau Phosphorylation and Cognitive Dysfunctions
Authors: Cheng Wai‐Yin , Ho Yuen‐Shan , Chang Raymond Chuen‐Chung
Published: December 2021

Background

Systemic inflammation has been linked to neuroinflammation and the progression of neurodegenerative diseases. Double‐stranded RNA‐dependent protein kinase (PKR) is a key signaling molecules that regulates immune responses by regulating macrophage activation, various inflammatory pathways, and formation of inflammasomes. This study aims at investigating whether PKR can be a pharmacological target to prevent both systemic inflammation‐triggered neuroinflammation, tau phosphorylation and cognitive dysfunctions.

Method

Laparotomy, a non‐bacterial endotoxin mouse model, is adopted to address the systemic inflammation triggered by surgery. Male wild‐type C57BL/6J and PKR‐KO mice were randomly divided into two groups: control group under sevoflurane anesthesia and laparotomy group under sevoflurane anesthesia. Expression of mRNA for cytokines and tau protein phosphorylation in different tissues was examined after laparotomy by quantitative RT‐PCR and western blot analysis respectively. Behavioral tests were also performed to examine the effects of laparotomy on cognitive functions.

Result

We have shown that laparotomy induced peripheral inflammation and neuroinflammation in male C57BL/6J mice. By genetic knockout of PKR in mice, it potently downregulated the increased IL‐1 expression induced by laparotomy in both the liver and frontal cortex at 4 h and day 1 after laparotomy. Meanwhile, knockout of PKR significantly reduced the laparotomy induced tau protein phosphorylation (AT8 and pS416) in the frontal cortex. Furthermore, in wild type mice, cognitive impairment was observed following laparotomy in terms of the decline in problem‐solving abilities, impaired short‐term and long term memory in the puzzle box test; reduced recognition memory with lower discrimination index in the novel object recognition test; and impaired spatial working memory with the reduced percentage of alteration in the spontaneous Y‐maze; while for PKR‐KO mice, cognitive flexibility, short‐term and long term memory recognition memory remained intact after laparotomy.

Conclusion

This study reveals that genetic knockout of PKR in mice could attenuate laparotomy induced systemic inflammation, neuroinflammation, abnormal tau phosphorylation and cognitive impairment.Further studies will be performed to examine the effect of knockout of PKR in macrophages and cholinergic neurons on systemic inflammation, neuroinflammation and cognitive functions.

Acknowledgement: The study is supported by General Research Fund (17123217) to RCCC.
Adaptive x‐ray techniques for coherent scattering from distributed amyloid targets in the brain
Authors: Breedlove Sophya , Badano Aldo
Published: December 2021

Background

Recently, spectral small‐angle x‐ray scattering (SAXS) techniques have been proposed for interrogating deep targets including amyloid plaques and other protein aggregates in the brain, which could aid in the early diagnosis of neurodegenerative diseases such as Alzheimer's disease.

Method

A model was developed to predict the main features of SAXS profiles from targets with varying shape, size and location corresponding to brain regions of interest. An optimization approach was devised adapting the beam orientation for improving deep target characterization. We calculate a figure of merit based on relative scattering intensity, scattering vector smearing , and path length.

Result

Increasing target size introduced additional signal smearing due to location uncertainty. Beam incidence angle and target shape affected the scattering profile by altering the path length or effective target size. For temporal and frontal lobe targets, beam effectiveness varied by up to 2 orders of magnitude.

Conclusion

Beam orientation optimization for coherent x‐ray scattering could allow a clinical implementation to target regions of interest while minimizing the radiation does to other radiosensitive areas of the head.
Type 2 Diabetes and association with neuropathological changes and domain specific cognitive decline
Authors: Karanth Shama D , Abner Erin L , Braithwaite Dejana , Fardo David W. , Nelson Peter T. , Katsumata Yuriko
Published: December 2021

Background

Type 2 Diabetes (T2DM) and Alzheimer’s disease (AD) are common diseases in aging populations in the US. Multiple large epidemiological studies suggest that T2DM is strongly associated with cognitive impairment. However, the association between T2DM and AD is still controversial. The current study was conducted to investigate the association of diabetes history with neuropathological and cognitive features.

Method

Participant data were drawn from the National Alzheimer’s Coordinating Center (NACC). Diabetes status was determined based on any reported diabetes diagnosis or diabetic treatment during annual assessments. Standardized z scores in memory, attention, language, and executive function were derived from neuropsychological test scores assessed at each annual visit. Multivariable linear mixed‐effects models assessed associations between cognitive domain scores and diabetes and APOE ε4 interaction adjusting for sex, age at each visit, education, hypertension, time and center. In a subset of 5190, autopsied participants, logistic regression was used to examine the association of diabetes and specific neuropathology changes adjusting for sex, age at death, education, hypertension, years of follow‐up and center.

Result

After excluding participants who reported any other type of diabetes, whose age at baseline were < 60 years, and who had missing APOE genotype data, diabetes was present in 4,899 participants (13.5%) with a mean age at last visit of 77.2 ±8.5 (Table 1). Participants with diabetes history had lower odds for AD neuropathology changes (ADNC), OR=0.77 (95% CI=0.63‐0.94). Diabetes history was associated with increased odds of brain infarcts/lacunes (OR=1.47 and 95% CI=1.21‐1.78) and moderate arteriosclerosis (OR=1.37 and 95%CI=1.05‐1.79). Diabetes history plus APOE ε4 allele was associated with lower attention domain scores (Figure 1).

Conclusion

Diabetes was positively associated with cerebrovascular pathology and negatively associated with ADNC. APOE ε4 genotype modified the association between diabetes and cognitive features.
Combinational therapy, concomitantly targeting post‐translational modified Aβ peptides and CD33, leads to an add‐on effect in passive immunotherapy
Authors: Gnoth Kathrin , Geissler Stefanie , Ilse Victoria , Rahfeld Jens‐Ulrich , Cynis Holger , Schilling Stephan
Published: December 2021

Background

Passive immunotherapy is a very promising approach for the treatment of Alzheimer’s disease (AD). We recently demonstrated that the antibody‐mediated targeting of isoD7‐modified Aβ peptides leads to the attenuation of AD‐like amyloid pathology in 5xFAD mice (Gnoth et al., 2020). Targeting post‐translationally modified Aβ peptides is a promising approach for reduction of effective therapeutic antibody amount and thereby decreasing treatment‐related side effects. Nevertheless, high dosing of monoclonal antibodies and appearance of side effects such as amyloid‐related imaging abnormalities (ARIAs) provide room for approaches such as combination therapies.

Method

We investigated the role of CD33 for Aβ phagocytosis in transgenic mice treated with an isoD7‐Aβ antibody. CD33 or sialic‐acid‐binding immunoglobulin‐like lectin 3 (Siglec‐3) is an inhibitory receptor molecule on the surface of brain microglia. We generated a new mouse line by crossing 5xFAD mice (Oakley et al., 2006) with CD33 knock out mice (Brinkman‐Van der Linden et al., 2003). This mouse line was then used for treatment studies with our anti‐isoD7‐Aβ antibody K11_IgG2a. Therefore, 3month‐old female 5xFAD and 5xFAD/CD33 mice were treated with 4 mg/kg K11_IgG2a and IgG2a isotype control. After 38 weeks treatment an Elevated Plus Maze (EPM) test have been performed, followed by the preparation of mouse brain and the read out by ELISA and Immunohistochemistry.

Result

We could demonstrate that CD33 knock out leads to the reduction of Aβ plaque load as well as the rescue of behavioral deficits in 5xFAD mice. Above that, we detected elevated amounts of plaque surrounding microglia in 5xFAD/CD33KO mice receiving antibody treatment, followed by an even more decrease of Aβ plaque load.

Conclusion

In summary, a combinational therapy, concomitantly targeting post‐translational modified Aβ peptides and CD33, leads to an add‐on effect in passive immunotherapy.