bluuebunny/crossref_metadata_2025 huggingface dataset:
Newest and successful therapy approach for Alzheimer's, dementia care: Rediscover recovery practical reference training
Authors: Mayer Gabriele
Published: December 2020

Background

Through minimized information all sensory organs activities/abilities real‐world/daily life, brain cells less “input”, pathological biochemical reactions/milieu, more slow down :perceptions, psycho‐social, brain functions, etc. Disorders: all perceptions, relationship disturbances. Social too fast, withdrawn activities, negative navigation, modern words. Persons lost relationship structures real‐world/daily life. Reactions: doing nothing, panic, aggressively, going down, abuse medications, internet, alcohol and needs help. Caregivers do best but in their structures. Thus withdraw activating “input” brain; “individually subjective selective‐ processing”, no consciousness/concentration in real‐world/daily life. Persons out of structures, fall backwards own development, status like babies. Perceptions less. Caregivers give structures, pathological circle.

Method

Practical working, with intermittent accompanied families, caregivers.

Result

Newest, successful “Rediscover Recovery Practical Reference Training” special knowledge, developed: Gabriele Mayer,‐ only in daily life/real‐world,‐ rebuilding person’s status. Training: orientation, ‐relationship to real‐world/daily life objects/subjects, doing little activities himself he can do, comment: ”well done”.‐Body scheme; consciousness/concentration.‐Relationship to himself (“I”). Do not with him tasks/duties only wants, can do in way he knows. Take older words he used. Brain works with older, covered up association fields, repeats call up older patterns. Person in daily life: verbally this in his words: activates brain cells, more perceptions “input”, relationship to real‐world/daily life doing. Family, caregivers: take over therapy by avoiding frustration, give place person, that he can do, if it’s right way daily life. The long‐term care: repeat therapy daily life/real‐world time/time, develop from child to own development stages. Higher perceptions all sensory organs, more “input” brain.

Conclusion

Psycho social Factors, Environment: After individual training person trains himself with social daily life/real‐world, more “input” brain, social environment takes contact. The technology: does not exist to deal with volume of connections information in real‐world quality full ranges “Input” for brain, brain cells connections. Abstract pictures are not be used to test Alzheimer’s, Dementia, etc. Illness in real‐world brain, test only with real‐world subjects/objects pictures with real‐world words. It needs therapy: “Rediscovery Recovery Practical Reference Training”, than can live life intermittent accompanied by someone else. Topics of interesting: See above, causes research publish: ”Rediscover Recovery Practical Reference Training” ISBN 978‐0‐9904836‐0‐1, in German: “Die Kombinationstherapie fuer Muskeln, Sehnen und Gelenke” ISBN 078‐3‐00‐018641‐7.
Exploring molecular biomarkers with potential prognostic value in longitudinal observational studies on Alzheimer’s disease
Authors: Vanmechelen Eugeen , Goossens Julie , Dewit Nele , Smirnov Denis S , Jacobs Dirk , Belbin Olivia , Alcolea Daniel , Lleó Alberto , Galasko Doug R
Published: December 2020

Background

Incorporation of biomarkers into the diagnosis of AD has shifted its disease definition from clinical dementia (on average 7 years) into a biological change that may span two decades of a human life. Synaptic biomarkers and neurofilament light (NfL) have shown some potential to predict stage and disease course, however few studies have combined these markers in larger sample sets.

Method

Negative controls, preclinical subjects (n=90), and subjects with MCI (n=57) and mild AD (n=46) from the longitudinal observational study at the UCSD Shirley‐Marcos ADRC (UCSD cohort) were tested for their biomarker levels. One molecular/synaptic marker, neuronal pentraxin 2 (NPTX2), is quantified in CSF with an ELISA containing two monoclonal antibodies (mAbs). We describe a newly developed NfL assay based on two mAbs that specifically targets the C‐terminus of coil 2a from human NfL. A third marker is synaptobrevin 2 (VAMP2), an essential component of the synaptic vesicle. Classical biomarkers such as t‐tau, β‐amyloid42 and synaptic markers SNAP25 and neurogranin were available for this sample set.

Result

As expected, CSF NfL levels increase gradually over the course of the disease, while VAMP2, as well as SNAP25 and neurogranin, shows a significant change in a stage of AD characterized by low Aβ42 and normal CSF tau and CSF NfL levels, thus suggesting that synaptic changes may precede overt neuronal (axonal) damage. CSF NPTX2 is a robust biochemical reflection of cognitive decline, as defined by California Verbal Learning Tests and Mattis Dementia Rating Scale and in contrast to all other fluid markers, it is not age‐dependent in control individuals.

Conclusion

Exploring all these biochemical markers in observational longitudinal studies suggests changes might delineate different stages in the disease process: (1) intracellular synaptic markers such as VAMP2, SNAP25 and neurogranin precede neuronal degeneration as defined by increased CSF tau and CSF NfL levels, while NPTX2 only begins to decrease towards late clinical stages, showing a robust correlation to cognitive decline. When further verified and/or validated in other well‐designed longitudinal studies, such prognostic biomarkers might define specific stages and predict the onset of specific pathophysiological progression during the long course of the disease.
Does sex impact neuropsychiatric symptom burden in APOε4 carriers with at‐risk cognitive conditions?
Authors: Dissanayake Andrew S , Bowie Christopher R , Butters Meryl A , Flint Alastair , Gallagher Damien , Golas Angela C , Herrmann Nathan , Kennedy James L , Kumar Sanjeev , Lanctot Krista L , Mah Linda , Mulsant Benoit H , Pollock Bruce G , Rajji Tarek K , Schweizer Tom A , Munoz David G , Fischer Corinne E ,   PACT‐MD Research Group
Published: December 2020

Background

The Apolipoprotein E (APOE) ε4 allele is a well‐established genetic risk factor of Alzheimer's disease (AD). While sex may play an important modulatory role in the association between APOε4 and certain neuropsychiatric symptoms (NPS) in AD1, it is unclear whether or not this risk extends to cognitively at‐risk populations with Mild Cognitive Impairment (MCI) or a history of Major Depressive Disorder (MDD). This cross‐sectional analysis compared NPS burden between males and females in a cohort of APOε4 carriers with at‐risk cognitive conditions of AD.

Method

We analyzed the Neuropsychiatric Inventory Questionnaire (NPI‐Q) data of 51 symptomatic APOε4 carriers (age = 71.9 ± 5.2) from the PACt‐MD cohort which was comprised of older persons from three at‐risk groups of AD: MCI; MDD without MCI; and MDD with MCI. We stratified participants by sex to compare their NPS severity. We tested whether there was a significant association between sex and i) NPI‐Q total score, and ii) NPI‐Q severity score. We chose not to stratify by zygosity or diagnosis due to the sample size.

Result

Female APOε4 carriers (n = 33, MNPI Total= 2.27, MNPI Severity = 3.55 ) had significantly higher NPI‐Q total scores(t = 2.15, df = 43.67, p = 0.037, d = 0.50) and significantly higher NPI‐Q severity scores (t = 2.06, df = 45.37, p = 0.044, d = 0.48) than male carriers (n = 18 , MNPI Total = 1.72, MNPI Severity = 2.44). There were no significant differences in the prevalence of certain NPS between male and female carriers.

Conclusion

Our findings support the need to further investigate whether sex influences the effect of APOε4 on NPS burden. Although female carriers showed significantly higher levels of NPS burden, aligning with previous findings1, our analysis was limited by the small number of symptomatic male carriers (n = 18). Thus, further studies with larger samples are needed to elucidate the interaction between sex and APOε4 status on NPS burden. References: Kim, J., Fischer, C. E., Schweizer, T. A., & Munoz, D. G. (2017). Gender and Pathology‐ Specific Effect of Apolipoprotein E Genotype on Psychosis in Alzheimer's Disease. Current Alzheimer research, 8, 834–840.
Investigating astrocytes as mediators of tau spread
Authors: Reid Matthew J ,   Wendy Noble Research Group
Published: December 2020

Background

Highly phosphorylated tau aggregates are believed to spread in a prion‐like manner through tauopathy brain. We set out to determine the characteristics of tau deposition in mice expressing wild‐type human 3R and 4R tau, following peripheral injection of tau extracts from different tauopathies. Tau accumulations identified around astrocytes in the experimental mice prompted us to develop a human astrocyte culture model to further investigate tau uptake and spread.

Method

Tau was isolated from human postmortem control (CTRL), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and Pick’s disease (PiD) brain. Extracts were injected intraperitoneally into 4‐month old wild‐type and htau mice, and at 18 month‐of‐age tissue was collected for biochemical and immunohistochemical assessment.

Human iPSCs were directed into neural progenitor cells and terminally plated as astrocytes using a previously established protocol. Astrocytes were characterised using RT‐qPCR and immunocytochemical assessment. Cultures were spiked with the previously derived pathogenic tau isolated from human tissue. Cells were analysed immunocytochemically for tau uptake.

Result

We found that peripheral injection of brain extracts from AD, PSP and PiD brain results in regional differences in the patterns of tau aggregate accumulation in the mouse brain. Some tau pathology was associated with ‘activated’ astrocytes, similar to the pathology observed in the corresponding human postmortem brain. Cultures of human astrocytes that express mature cell markers were established.

Conclusion

Our data suggests that neurons in different regions are susceptible to different species of tau aggregates. It is possible that this might hint towards selective vulnerability in different tauopathies. The association of tau pathology with astrocytes in some cases suggests that astrocytes may play a role in tau spread. Our human astrocyte cultures will provide a model to determine how astrocytes may facilitate the spread of tau and potentially contribute to selective regional vulnerability in tauopathies.
Targeting porphyromonas gingivalis to treat Alzheimer’s disease and comorbid cardiovascular disease
Authors: Ermini Florian , Rojas Paola , Dean Afsah , Stephens Danielle , Patel Michele , Haditsch Ursula , Roth Theresa , Rodriguez Leo , Broce Sean , Raha Debasish , Nguyen Mai , Kapur Shirin , Lynch Casey C , Dominy Stephen S , Holsinger Leslie J , Hasturk Hatice
Published: December 2020

Background

We recently demonstrated the presence of the bacterial pathogen, Porphyromonas gingivalis (Pg), and its protease virulence factors, known as gingipains, in greater than 90% of AD brains. Brain gingipain levels significantly correlated with AD diagnosis and tau and ubiquitin pathology. Mechanistic studies in wild type mice demonstrated that Pg invades the brain after infection of the oral cavity, resulting in the development of neuropathology consistent with that of AD. These effects were blocked in mice after oral administration of the gingipain inhibitor COR388. In addition to neuropathology, AD is often accompanied by the comorbidity of cardiovascular disease. Pg has been linked to the development of atherosclerosis and the bacteria are found abundant within atheromatous plaque. We investigated if COR388 was efficacious in treating Pg‐accelerated atherosclerosis in a rabbit model.

Method

Eighteen New Zealand White rabbits on a 13‐week regimen of 0.5% cholesterol diet to induce atherosclerosis were randomized in the study. Twelve rabbits were orally infected with Pg 3x/week for 6 weeks for oral disease induction and 6 rabbits were sham‐infected. Six Pg –infected rabbits were orally administered COR388 10mg/kg once daily for the entire 13 weeks of the study (prevention protocol), and 6 Pg‐infected rabbits received vehicle for 13 weeks. Six sham‐infected rabbits received vehicle for 13 weeks. At 13 weeks, atherosclerotic plaques were quantified by assessing Sudan IV staining, histology, and ex vivo MRI. Serum levels of C‐reactive protein (CRP) were evaluated as a measure of systemic inflammation.

Result

Pg‐infected rabbits exhibited accelerated atherosclerotic disease severity than sham‐infected animals. COR388 diminished this atherogenesis compared to vehicle controls as evidenced by significantly less arterial plaque and a lower intima/media ratio. COR388 treatment also significantly reduced systemic levels of CRP.

Conclusion

COR388, a novel lysine‐gingipain inhibitor, is currently being tested in a Phase 2/3 clinical trial to target Pg for the treatment of AD. Based on the current preclinical data reported here, COR388 has the potential to attenuate atheroma formation and systemic inflammation in Pg‐ induced atherosclerosis and therefore may have beneficial effects on comorbid cardiovascular disease in Pg‐associated AD.
A patient journey analysis: Identification and treatment of dementia with Lewy bodies
Authors: Abler Victor , Rashid Nazia , Skoog Ben , Halpern Rachel , Bunner Scott , Frazer Monica S.
Published: December 2020

Background

Between 3.2%‐7.1% of dementia patients are diagnosed with DLB. There is limited research on the identification and treatment of DLB, indicating an unmet need for this condition.[2] [1] Hogan D, Fiest K, Roberts J, Maxwell C, Dykeman J, Pringsheim T, Jetté N. (2016). The Prevalence and Incidence of Dementia with Lewy Bodies: A Systematic Review. Canadian Journal of Neurological Sciences / Journal Canadien Des Sciences Neurologiques, 43(S1), S83‐S95. doi:10.1017/cjn.2016.2. [2] Monfared A, Meier G, Perry R, Joe D. Burden of disease and current management of Dementia with Lewy Bodies: a literature review. Neurol Ther, 2019, 8:289‐305.

Method

This claims‐data analysis examined commercial and Medicare Advantage with Part D (MAPD) enrollees aged ≥40 years with ≥2 DLB diagnoses from 01Jun2016–31May2018. The earliest DLB diagnosis was the index date. Continuous insurance enrollment was required from 24 months before to 12 months after index. Patient characteristics, diagnoses, medication utilization, symptoms (e.g. behavioral, movement changes), and imaging tests were measured in 6‐month periods pre‐ and post‐index.

Result

The 974 patients identified had mean age of 78.3 years, were 56.6% male, 90.0% were MAPD enrollees, and had a mean Charlson comorbidity score of 2.87 (SD=2.05). Generally, percentages of patients with ≥1 diagnosis in a dementia or symptom change category or with ≥1 pharmacy fill for an antipsychotic or behavioral health (BH) medication (e.g., antidepressants, anxiolytics) trended higher in each 6‐month period prior to index date, were highest in the 6 months beginning on index, and decreased slightly 7‐12 months post‐index. Across periods, 31%‐90% of patients had multiple types of dementia diagnoses. BH medications (52.4%‐63.9% with ≥1 BH medication fill across periods) were prescribed to DLB patients more often than were antipsychotics (14.2%‐31.5% with ≥1 antipsychotic fill). CT scans (10.6%‐27.5%) and MRIs (5.3%‐13.0%) were the most prevalent imaging tests.

Conclusion

Percentages of patients with imaging tests, DLB symptoms, diagnoses and treatments for DLB increased as patients’ first DLB diagnosis neared and occurred at lower percentages 7‐12 months after initial diagnosis.
Healthcare costs among patients with dementia‐related psychosis: Comparing dementia with Lewy bodies with other dementias
Authors: Abler Victor , Rashid Nazia , Skoog Ben , Halpern Rachel , Bunner Scott , Frazer Monica S
Published: December 2020

Background

DLB is the second‐most common form of degenerative dementia and it’s unclear whether healthcare costs differ for patients with DLB and Alzheimer’s disease. [1],[2]. The differential presentation of psychosis among dementias[3] may affect healthcare costs. [1] Bostrom F, Jonsson L, Minthon L, Londos E. Patients with Lewy body dementia use more resources than those with Alzheimer’s disease. Int J Geriatr Psychiatry 2007;22(8):713‐719. [2] Zhu CW, Scarmeas N, Stavitsky D, Albert M, Brandt J, Blacker D, Sano M, Stern Y. Comparison of costs of care between patients with Alzheimer’s disease and dementia with Lewy Bodies, Alzheimer’s Dementia, July 2008; 4(4):280‐284. [3] Tzeng R, Tsai C, Wang C, Wang T, Chiu P. Delusions in patients with dementia with Lewy bodies and the associated factors. Behavioural Neurology, 2018:1‐8.

Method

This claims data analysis examined commercial and Medicare Advantage with Part D (MAPD) enrollees aged ≥40 years with evidence of psychosis (antipsychotic (AP) treatment lasting ≥45 days or ≥1 AP pharmacy fill+≥1 psychosis diagnosis) and ≥2 diagnoses for the same type of dementia from 01Jun2016–31May2018. The earliest AP fill was the index date. Continuous insurance enrollment was required for 12 months before and after index. DRP and DLB patients were matched 1:1. Patient characteristics and healthcare costs were analyzed descriptively.

Result

Matched DLB and DRP cohorts (n=442 each) had average age of 78.3 years, were 53.6% male, and 89.8% had MAPD coverage. 44% of DRP patients had ≥2 Alzheimer’s diagnoses and 32% had ≥2 unspecified dementia diagnoses. DLB patients had a significant pre‐index to post‐index increase for total all‐cause healthcare costs (from $5,392 to $8,046, p<0.01) while pre/post differences among DRP patients were not significant. DLB patients had significantly higher mean post‐index pharmacy costs for all‐cause ($6,616 vs. $4,515), dementia‐related ($810 vs. $675) and psychosis‐related ($2,344 vs. $623) medications, and higher mean psychosis‐related total healthcare costs ($5,801 vs. $2,687) than DRP.

Conclusion

DLB patients had higher medication and psychosis‐related costs than DRP patients who had other dementias.
Dually targeting human soluble epoxide hydrolase and P38 kinase to prevent neuroinflammation for the treatment of Alzheimer’s disease
Authors: Liang Zhibin , Zhang Bei , Xu Meng , Morisseau Christophe , Hwang Sung Hee , Hammock Bruce D. , Li Qing X.
Published: December 2020

Background

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with no cures. While many pathological characteristics occur in the AD brain, neuroinflammation is a prevalent pathogenic stress that leads to neuronal death in AD. Targeting the brain inflammation to keep neurons alive is an attractive therapeutic strategy for AD. TPPU is a potent inhibitor of soluble epoxide hydrolase (sEH) and can enter into the brain. It has a good efficacy on many chronic inflammatory diseases in preclinical animal models ranging from mice to nonhuman primates. For central nervous system disorders, TPPU shows therapeutic effects in rodent models of neuropsychiatric syndromes associated with inflammation such as stroke, seizure, depression, and Parkinson’s disease. However, the anti‐neuroinflammatory effects and underlying mechanisms of TPPU for potential AD interventions remain elusive.

Methods

With an aim to develop multi‐targeted therapeutics for AD, TPPU was screened in enzymatic assays against sEHs from different mammalian species and a broad panel of human kinases for potential new targets relevant to neuroinflammation. To elucidate the molecular mechanisms, we established an AD cell model using human differentiated SH‐SY5Y nerve cells exposed to toxic amyloid oligomers and investigated the neuroprotective effects of TPPU. Cell viability was assessed by the MTS assay. The cellular levels of sEH and p38β kinase were evaluated by immunoblotting. Tau hyperphosphorylation and nuclear NF‐κB activation were assessed by ELISA. Mitochondrial function was assessed by the mitochondrial membrane potential assay.

Results

TPPU inhibits both human sEH and p38β kinase, two master regulators of inflammation, with nanomolar potencies and distinct selectivity. TPPU effectively prevents neuronal death by mitigating amyloid toxicity, tau hyperphosphorylation and mitochondrial dysfunction, promoting neurite outgrowth, and suppressing activation and nuclear translocation of NF‐κB for inflammatory responses in human nerve cell culture. Pairwise treatment of different selective inhibitors of sEH and p38 kinase synergizes neuroprotection, the effect of which is comparable to the TPPU treatment alone.

Conclusions

The study supports the argument that sEH is a novel target of AD worth pursuing. It uncovers the potential of TPPU and other sEH/p38β dual inhibitors as disease‐modifying agents targeting neuroinflammation for the treatment of Alzheimer’s disease and related CNS disorders.
Anesthesia and surgery induce age‐dependent changes in postoperative delirium behaviors and microbiota
Authors: Liufu Ning , Liu Ling , Xie Zhongcong , Zhang Yiying
Published: December 2020

Background

Delirium is the most common postoperative complication in senior patients and is associated with accelerated cognitive decline and Alzheimer's disease and related dementia (ADRD). However, the neuropathogenesis of POD remains mostly unknown and no effective medication to prevent or treat POD. Gut microbiota dysbiosis, a condition of microbiota imbalance or maladaptation inside the gut, which could lead to altered immune functions and associated with disorders of POD. Aging and neuroinflammation may also contribute to the neuropathogenesis of POD. However, while all patients may have neuroinflammation, not all patients develop POD. Thus, neuroinflammation alone (single‐factor model of postoperative delirium) is not sufficient to cause POD. Therefore, the objective of the current study was to test the hypothesis that anesthesia/surgery causes age‐dependent gut microbiota dysbiosis, changes in brain IL‐6 level, and mitochondrial function, leading to postoperative delirium‐like behavior in mice.

Method

Female 9 or 18 months old mice received abdominal surgery under 1.4% isoflurane for two hours. We employed a battery of natural and learned behavioral tests to determine the delirium‐like behavior, assessed the gut microbiota before and after the anesthesia/surgery by gene pyrosequencing of 16S rRNA, and measured levels of brain IL‐6(ELISA), synaptic marker( Western blot ) and mitochondrial function (Seahorse XFp Extracellular Flux Analyzer) as measures of neuroinflammation and cerebral dysfunction. For intervention, intragastric administration of lactobacillus and probiotic were used to mitigate the anesthesia/surgery‐induced above changes.

Result

Anesthesia/surgery caused different alterations in gut microbiota, including change rate of reduction in the levels of gut lactobacillus, between the 18 and 9 months old mice. The anesthesia/surgery induced greater postoperative delirium‐like behavior, increased brain IL‐6 levels, decreased PSD‐95 and synaptophysin levels, and mitochondrial dysfunction in 18 than 9 months old mice. Treatments with lactobacillus and probiotic mitigated the anesthesia/surgery‐induced changes.

Conclusion

We demonstrated that anesthesia/surgery induces age‐dependent changes in the gut microbiota(reduction in lactobacillus), increases brain levels of IL‐6, decreases levels of synaptic marker, and reduces mitochondrial function while also promoting the development of postoperative delirium‐like behaviors in the mice. Treatment with lactobacillus or probiotic mitigated these detrimental effects, strongly suggesting that abnormalities in the gut microbiota contribute to the development of postoperative delirium.
Cognitive differences between healthy monolingual and bilingual anglophones on the English version of the Dépistage Cognitif de Québec: A new screening tool for atypical dementia
Authors: Lévesque Marianne , Ouellet Marie‐Christine , Meilleur‐Durand Synthia , Bouchard Rémi W. , Verret Louis , Fortin Marie‐Pierre , Nadeau Yannick , Molin Pierre , Caron Stéphanie , Hudon Carol , Masellis Mario , Cunnane Stephen , Villeneuve Sylvia , Gauthier Serge , Callahan Brandy L. , Jarrett Pamela , Hsiung Ging‐Yuek Robin , Laforce Robert
Published: December 2020

Background

Cognitive abilities between monolingual and bilingual individuals may differ, making it important to validate new cognitive screening tools using psychometric testing. Otherwise assessments could be subject to misinterpretation, leading to inaccurate diagnoses. The current project aimed to compare healthy older monolingual and bilingual anglophones on the English version of a new cognitive screening test designed for better recognition of atypical dementia; the Dépistage Cognitif de Québec (DCQ, www.dcqtest.org). The DCQ was developed at la Clinique Interdisciplinaire de mémoire de Québec, and its psychometric properties have been well studied, including its sensitivity and specificity to detect atypical dementia compared to current standardized cognitive screening tests (Laforce et al., 2018; Sellami et al., 2018).

Methods

The DCQ was administered by qualified psychometricians to 85 healthy native English‐speaking participants aged 50 years and over, in various sites across North America. The Montreal Cognitive Assessment (MoCA) was used to determine participants’ eligibility. Language proficiency was established using the Language Experience and Proficiency Questionnaire (LEAP‐Q).

Results

Amidst the anglophone participants recruited, 30 monolingual anglophones and 29 bilingual anglophones met the inclusion criteria. The two groups had similar age, education and MoCA scores. Monolinguals and bilinguals were compared on their total DCQ scores as well as on each of the 5 indexes of the DCQ: Memory, Visuospatial, Executive, Language and Behavioural. Statistical analysis showed a significant advantage for the bilingual participants on the total DCQ scores and on the Language index, which was later washed out following a Bonferroni correction. No significant differences were found between groups on any of the other indexes.

Conclusion

This study is the first to explore psychometric properties of the DCQ in older monolingual and bilingual participants tested in their native language. The results highlight the importance of identifying and characterizing linguistic diversity before using new screening tools in clinical settings. The potential cognitive advantages of bilingualism, even in healthy older adults, should be considered when interpreting test data and explicitly discussed in neuropsychological reports. Similar studies should be conducted for all future cognitive screening measures, especially to further examine the differences between groups on language‐related tasks.
Investigating P2X7R‐mediated inflammatory signalling in Alzheimer's disease
Authors: Lobo Paula Beltran , Perez‐Nievas Beatriz G , Noble Wendy
Published: December 2020

Background

Glial function is altered in Alzheimer’s disease (AD) in response to danger‐associated molecular patterns in the local environment such as the binding of Aβ species to toll‐like and purinergic receptors, including P2X7R. These interactions activate pro‐inflammatory pathways and lead to the release of cytokines and chemokines that participate in damaging inter‐cellular cascades. In vivo AD models have shown beneficial effects following P2X7R inhibition via mechanisms that could prevent pathological tau changes. However, the effects of P2X7R activation and downstream inflammatory signalling on tau‐mediated neurodegeneration in AD remains unknown.

Method

We have used biochemical and immunohistochemical methods in post‐mortem control and AD BA9 prefrontal cortex to examine changes in P2X7R expression, determine the spatial pattern of P2X7R activation relative to Aβ and pathological tau accumulation and evaluate the association between P2X7R and local inflammatory responses. Primaryglial and organotypic slice culturesare being used to model glial responses to physiological Aβ species and the downstream consequences on neurons.

Result

We found elevated levels of P2X7R from Braak stage II relative to controls associated with an increased plaque burden, mislocalization of tau to the synapses and astrocyte reactivity. P2X7R was markedly expressed in astrocytes surrounding AD hallmarks and also in disease‐associated microglia neighbouring Aβ plaques. Investigation of inflammatory mediators linked with P2X7R‐positive glia revealed higher activation of the NLRP3 inflammasome and NFκB pathways with disease progression. Preliminary in vitro and ex vivo models suggest that pathological changes in tau following Aβ stimulation are related to P2X7R‐inflammatory activity.

Conclusion

These data suggest that P2X7 receptor expression and activation is altered in the early stages of AD, prior to marked synapse loss. Ongoing studies are aimed at determining if blockade of P2X7R‐mediated inflammatory changes in has benefit in models of AD.
Create music at home: Meeting psycho‐social needs through music interventions for people with dementia and their caregivers
Authors: Ray Kendra , Mittelman Mary S
Published: December 2020

Background

For people with dementia and their caregivers, neuro‐psychiatric symptoms of dementia may have a negative affect on quality of life. Some studies have shown positive effects of music listening, singing and other individualized music‐based interventions. This study presents a solution by creating opportunities for family caregivers to provide non‐pharmacological uses of music during caregiving activities in the home setting.

Method

A psycho‐educational, music‐based protocol for caregivers to use therapeutic music for their family member with dementia was written. Nine dyads (caregiver and care receiver) were recruited from home‐based settings in the NYC area. Family caregivers were educated with hands‐on education in a classroom setting with a music therapist one time per week for one‐hour for six weeks. Using the Cornell‐Brown Scale for Quality of Life in Dementia, quality of life for the care receiver with dementia was measured pre‐test and post‐test the 6‐week psycho‐educational training.

Result

A paired samples t‐test indicated a significant increase in quality of life in care receivers with dementia from baseline to following the 6‐week psycho‐educational, music‐based protocol, p = .003. In this presentation, we will discuss the interventions taught to caregivers to facilitate in the home setting with their care receiver diagnosed with dementia. We will present use of technology to adjust study protocol made due to COVID‐19.

Conclusion

Although this study is ongoing, our findings suggest that caregivers can implement music‐based interventions that may lead to an increase in quality of life for their family member with dementia.
The incidence of dementia‐related psychosis in people with dementia: Results from a survey of 302 U.S. healthcare providers
Authors: Chen Jeanny , Bell Stephen , Brain Cecilia
Published: December 2020

Background

In the U.S., the incidence of dementia‐related psychosis (i.e., hallucinations and delusions) among people with dementia has been estimated at 30%.1‐15 However, it is hypothesized that the lack of a diagnostic code and approved medications for dementia‐related psychosis has resulted in considerable under‐recognition of the symptoms. It is possible that the actual incidence of dementia‐related psychosis is much higher than 30%.

Method

302 U.S. healthcare providers (HCPs)—physicians, nurse practitioners, and physician assistants—completed an online survey in which they were asked to estimate the percentages of their patients with dementia who have (a) hallucinations and/or delusions; (b) neuropsychiatric symptoms not including hallucinations or delusions (e.g., aggression, agitation, depression, sleep disturbances, anxiety); or, (c) no neuropsychiatric symptoms. Survey respondents were also asked to provide medical chart data for the last 8 (n=2416) treated patients with dementia and neuropsychiatric symptoms. HCPs were asked several questions about each chart, including which specific neuropsychiatric symptoms the patient had at the last consultation. As part of the data analysis, the percentage of the 2416 charts in which the patient had hallucinations, or delusions, or both, was computed.

Result

The mean percentages of patients with dementia who had: (a) hallucinations and delusions; (b) neuropsychiatric symptoms not including hallucinations or delusions; and, (c) no neuropsychiatric symptoms, were (a) 44%, (b) 36% and (c) 20% respectively. When asked in the survey to only consider the dementia population with any neuropsychiatric symptoms the HCPs’ estimate of delusions and hallucinations was 55% (calculated as 44%/(44%+36%)). Based on the medical charts, 57% of patients with dementia and neuropsychiatric symptoms had hallucinations and/or delusions, which is close to the HCP’s estimate of 55%.

Conclusion

U.S. HCPs estimate that 44% of their patients with dementia have hallucinations and/delusions—an incidence much higher than the previously assumed one‐third. Results from a large sample of medical charts attest to the accuracy of the HCPs' estimate.
RIN3 Binds to BIN1 and CD2AP to increase APP‐CTFS in early endosomes
Authors: Shen Ruinan , Wu Chengbiao
Published: December 2020

Background

About one‐third of the genes related to Alzheimer’s disease (AD) identified by GWAS encode proteins that function predominantly in the endocytic pathways. Among them, the Ras and Rab Interactor 3, RIN3 is a guanine nucleotide exchange factors (GEFs) for the Rab5 small GTPase family and has been implicated to be a risk factor for both late onset AD (LOAD) and sporadic early onset AD (sEOAD). However, how RIN3 is linked to AD pathogenesis is currently undefined.

Methods

Quantitative PCR and immunoblotting were used to measure gene expression levels in mouse brain, cultured basal forebrain cholinergic neuron (BFCNs) or PC12 cells. Immunostaining was used to define subcellular localization of RIN3 and visualize endosomal changes in cultured primary BFCNs and PC12 cells. Recombination RIN3‐flag‐tagged protein was purified from HEK293T cells and was used to define RIN3‐interactomes by mass spectrometry. Live imaging of primary neurons was used to examine axonal transport.

Results

Expression of RIN3 was upregulated in the brain tissues of young APP/PS1 mice. The increase was specific for the hippocampus and cortex since RIN3 expression level did not show an increase in either the olfactory bulb or the cerebellum. RIN3 mRNA level was also found to be elevated in embryonic day (E18) 18 in primary basal forebrain cholinergic neurons (BFCNs) cultured from APP/PS1 mouse. Concomitant early endosome enlargement was seen in these BFCNs. We have demonstrated that RIN3 interacted with two other AD risk factors: BIN1(bridging integrator 1) and CD2AP (CD2 associated protein). Both BIN1 and CD2AP were recruited to early endosomes through binding to the proline rich domain (PRD) of RIN3. Overexpression of RIN3 or CD2AP promoted APP cleavage to increase APP carboxyl terminal fragments (CTFs) in PC12 cells, while upregulating RIN3 or BIN1 neuronal isoform increase phosphorylated Tau level. The effect of upregulation of RIN3 expression to increase APP CTFs was ameliorated by a dominant negative Rab5 construct (Rab5S34N). Increased expression of RIN3 impaired axonal trafficking of both APP and BACE1.

Conclusion

RIN3 is significantly unregulated and correlated with endosomal dysfunction in APP/PS1 mouse. Through interacting with BIN1 and CD2AP, increased RIN3 expression alters axonal trafficking and procession of APP.
Treatment patterns and needs for dementia‐related psychosis described by patients and care partners (caregivers): An observational, prospective study to describe the patient experience
Authors: Brandt Teresa , Frangiosa Theresa , Biggar Virginia , Taylor Angela , Keller Bill , Abler Victor
Published: December 2020

Background

We aimed to describe current treatment patterns and unmet needs of persons with DRP from a patient and care partner (CP) perspective.

Methods

This observational, non‐interventional, prospective study used a mixed‐methods approach with qualitative interviews and a quantitative online survey. Persons with DRP and CP of persons with DRP reported the effectiveness of current treatments using a visual analog scale (VAS) of 0 (“not at all well”) to 5 (“extremely well”) and ranked benefits of an ideal treatment. CP burden was outside the scope of this study.

Results

The qualitative interview was completed by 1 patient and 15 CP. Current treatments included atypical antipsychotics, antidepressants, anxiolytics, and benzodiazepines. Participants commonly indicated a need to improve patients’ ability to know what is real vs not real. The online survey was completed by 26 patients and 186 CP on behalf of patients under their care. Common treatments used included atypical antipsychotics (27% of patients, 41% of CP) and psychological/ behavioral therapy (23% of patients, 8% of CP). Many participants reported no current treatment (42% of patients, 42% of CP). Participants reported that current treatment methods were less than moderately helpful in treating patients’ most impactful symptoms with a median VAS score of 2.0/5 reported by patients and CP (mean VAS score [standard deviation] = 2.33 [1.0] for patients [n=15], mean [standard deviation] VAS score = 2.4 [1.3] for CP [n=104]). Discontinuation of a treatment was reported by 11 patients and 115 CP, most commonly due to a side effect (27% of patients, 31% of CP), doctor’s recommendation (27% of patients, 14% of CP), or lack of symptom improvement (9% of patients, 28% of CP). Participants ranked the ability to distinguish what is real vs not real (35% of patients, 49% of CP) and overall symptom improvement (42% of patients, 23% of CP) as the most important benefits of an ideal treatment (Figures 1 and 2).

Conclusions

Patients and CPs reported either not taking any DRP treatments or that current treatments were associated with side effects along with limited efficacy. There is an unmet need for safe and effective treatments for DRP.
Cytoplasmic expression of TDP‐43 decreases global translation both in vitro and in vivo
Authors: Charif Santiago Elias , Luchelli Luciana , Vila Antonela , Blaustein Matías , Igaz Lionel Muller
Published: December 2020

Background

TDP‐43 is a major component of cytoplasmic inclusions observed in neurodegenerative diseases like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). To further understand the role of this predominantly nuclear RNA‐binding protein in disease‐related mRNA/protein metabolism and proteostasis, we used a combined approach with cellular and animal models that overexpress a cytoplasmic form of human TDP‐43 (TDP‐43‐ΔNLS), recapitulating ALS/FTD features.

Method

HEK293 cells were transfected with empty vector or hTDP‐43‐ΔNLS followed by a method for labeling de novo translation, surface sensing of translation (SUnSET), based on puromycin (PURO) incorporation. We also assessed whether cytoplasmic TDP‐43 regulates global translation in vivo using a transgenic TDP‐43‐ΔNLS mouse model. Brain cortices from control and transgenic mice were subjected to polysome profiling and western blotting. Lastly, cellular level analysis of ongoing protein synthesis was performed by applying the SUnSET method in acute thick brain slices from control and TDP‐43‐ΔNLS mice. Immunofluorescence for TDP‐43 and PURO was performed and signal intensity was measured.

Result

Our in vitro approach showed that, while control cells displayed robust puromycilation, TDP‐43‐ΔNLS positive cells exhibited reduced ongoing protein synthesis when compared to control groups. In vivo results from polysome profiling revealed a shift towards light (non‐polysomal) fractions as compared to wild‐type littermates, indicating a decrease in global mRNA translation. Cellular level analysis of ongoing protein synthesis showed that slices from control mice incubated with PURO exhibited robust cytoplasmic PURO signal in layer 5 neurons from motor cortex, and normal nuclear TDP‐43 levels similar to control (‐PURO) neurons. Slices from TDP‐43‐ΔNLS mice incubated with PURO exhibited high cytoplasmic expression of TDP‐43 and a reduction in puromycilation respect to control mice. Quantification of neuronal staining intensity revealed a significant decrease in PURO incorporation in transgenic vs. control mice.

Conclusion

In vitro and in vivo results indicate that cytoplasmic TDP‐43 can decrease global translation and potentially cause functional/cytotoxic effects as observed in ALS/FTD. We provide in vivo evidence (by two independent and complementary methods) for a role of mislocalized TDP‐43 in the regulation of global protein synthesis, with implications for understanding the molecular changes underlying the clinic‐pathological manifestations of TDP‐43 proteinopathies.
Employing an in vitro biosensor assay to investigate tau seeding kinetics within cases of sporadic Alzheimer disease and in a model of tauopathy
Authors: Kamath Tarun V , Commins Caitlin , Klickstein Naomi , Oakley Derek , Hyman Bradley T , Dujardin Simon
Published: December 2020

Background

Tauopathies such as Alzheimer’s disease (AD) are characterized by tau aggregation in the brain (Kovacs, 2015). Recent studies have suggested that tau aggregation occurs via the trans‐synaptic spread of certain tau species and subsequent aggregation via contact between these seeds and non‐aggregated tau (Mudher et al., 2017). Tau seeds can be isolated from many sources, including the brains of humans with tauopathies and tau‐transgenic mice (Clavaguera et al., 2009; Holmes et al., 2014; Iba et al., 2013; Kaufman et al., 2016). Here, we aimed to understand if the kinetics of tau seeding could inform us on the properties of initial seeds.

Method

Brain extracts containing tau seeds from 32 patients with sporadic AD and the rTg4510 mouse model of tauopathy were incubated with a well‐described FRET‐biosensor tau seeding assay. The cells were imaged for 48 hours and analyzed for aggregate count and morphology.

Result

Aggregate formation followed a logistic function over time, with a lag phase, exponential rise phase, and plateau phase. We investigated the properties of these phases by increasing the concentration of tau seeds added to the assay, which led to a parallel increase in the magnitude of the plateau phase and slope of the exponential rise phase, until a ceiling. Across cases of sporadic AD, the length of the lag phase was inversely correlated with the magnitude of the plateau phase. Finally, when initiating aggregation using tau seeds from the rTg4510 mouse, aggregation was several fold higher in the plateau phase than any case of sporadic AD, with significantly altered aggregate morphology which was not observed across the human AD aggregates.

Conclusion

The definition of a strain of tau has long been dominated by structural variation – aggregates with different morphologies are thought to be of different strains (Sanders et al., 2014; Kaufman et al., 2016). We present here an alternative method of classifying aggregates based not just on morphology but on aggregation kinetics which we believe reflect biochemical and biophysical properties. This analysis reveals that contrary to previous reports, within cases of sporadic Alzheimer’s disease, there may exist multiple strains of tau leading to variations in aggregate formation kinetics.
Association of APOE genotype and lipid lowering with cognitive function in a randomized placebo‐controlled trial of Evolocumab
Authors: Korthauer Laura E , Giugliano Robert , Guo Jianping , Sabatine Marc , Sever Peter , Keech Anthony , Pedersen Terje , Kurtz Christopher , Ruff Christian , Mach Francois , Ott Brian R
Published: December 2020

Background

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher cholesterol levels, ß‐amyloid burden, and risk of Alzheimer’s disease (AD). A recent pooled re‐analysis of clinical trials (Geifman et al., 2017) found that long‐term use of cholesterol‐lowering medications may lower rates of cognitive decline in patients with mild to moderate AD, with potentially greater therapeutic efficacy for ε4/ε4 carriers. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. The purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab, LDL cholesterol level, and cognitive function.

Method

Of 16,174 APOE‐genotyped patients (25.8% with one ε4 allele; 2.3% with two ε4 alleles) from FOURIER, a randomized, placebo‐controlled trial of evolocumab added to statin therapy, 13,481 completed the Everyday Cognition Scale (ECog) to report subjective cognitive changes from the end of the trial compared to its beginning (scores ≥2 reflect subjective decline). A subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial.

Result

There was a dose‐dependent relationship between APOE ε4 genotype and subjective memory decline on the ECog in the placebo arm (p = .009; ε4/ε4 carriers vs. non‐carriers: OR = 1.38, 95% CI [.98,1.95]) but not the evolocumab arm (p = .77, OR = 1.14, 95% CI [.81,1.60]). However, the genotype x treatment interactions were not significant, likely due to a limited number of ε4/ε4 carriers. After adjustment for demographic and medical covariates, APOE genotype did not significantly moderate the relationships between treatment arm or post‐baseline LDL cholesterol level on CANTAB performance (p’s>.05) in the subset examined.

Conclusion

APOE genotype did not significantly moderate the relationship between evolocumab treatment and cognitive function, although analyses were limited by the low population frequency of the ε4/ε4 genotype. This supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol‐lowering medications in people at genetic risk for Alzheimer’s disease.
Engaging rural older minority adults in dementia research during a pandemic‐associated quarantine
Authors: Wiese Lisa Kirk , Lingler Jennifer , Williams Ishan Canty , Schoenberg Nancy E , Galvin James E
Published: December 2020

Background

Rural‐dwelling individuals are at heightened risk for dementia syndromes as they age. Recognizing that faith institutions are bulwarks in rural communities, we partnered with churches to design research that aims to improve knowledge of, and promote screening for, dementia. Since recruitment began just as COVID‐19 emerged, in‐person recruitment ceased. We developed a virtual protocol to train health educators and engage rural, racially diverse congregants.

Method

Guided by Schoenberg’s (2011) “Faith Moves Mountains” model, health educators were trained via videoconferencing, using Alzheimer’s Association online English/Spanish resources. Educators approached 35 congregants to administer telephone‐based teaching, pre‐post tests of dementia knowledge, and dementia screening.

Results

Thirty rural older adults responded to faith health educator tele‐recruitment and intervention. Pre‐post knowledge surveys showed significant improvement (r=.67, p=.04). Thirteen (43%) completed dementia screening, followed by referral to a memory telehealth clinic.

Conclusion

This faith‐based model shows promise for reaching isolated rural residents facing dementia risk.