bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal changes in FAQ scores by informant relationship
Authors: Culhane Jessica E. , Teylan Merilee , Gauthreaux Kathryn , Chen Yen‐Chi , Chan Kwun Chuen Gary , Mock Charles , Kukull Walter A.
Published: December 2020

Background

Informant reports are assumed to reduce bias associated with self‐report of patients’ neurocognitive conditions, aiding clinicians in diagnosis. Prior studies have indicated that bias in informant reports may exist depending on relationship to the participant (spouse vs child). The Functional Assessment Questionnaire (FAQ) is an informant report of subjects’ functional ability in several domains. We investigated whether there are differences in FAQ score by informant relationship.

Method

We included participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) who had at least three visits with the same informant (spouse or child) and completed the FAQ. Using general linear and linear mixed models, we estimated the cross‐sectional difference in FAQ scores by informant relationship as well as the difference in the slope of FAQ scores over time, adjusting for participant and informant demographics, participant cognition, and participant residence type. We also evaluated whether there were differences in objective cognitive test scores over time by informant relationship using the Mini‐Mental State Exam (MMSE).

Result

Of the 6,815 participants that met inclusion criteria, 77% had a spouse informant. At their initial visit, participants with a spouse informant were more likely to be younger, male, white, more educated, and living at home. In adjusted cross‐sectional analysis, spouse informants reported worse functional ability (higher FAQ score) than child informants (1.12 points, 95% CI: 0.74–1.51). In the adjusted longitudinal model, FAQ score increased 1.34 points per year (95% CI: 1.13– 1.55), and the FAQ score was an additional 0.15 points higher per year (95% CI: 0.02– 0.28) for participants with a spouse informant. However, participants with a spouse informant also had MMSE scores that were worse (0.26 points lower per year) compared to those with a child informant.

Conclusion

The relationship of the informant to the participant may affect reporting on the FAQ. Cross‐sectionally, spouses of participants report higher FAQ scores (worse functional ability) than children, adjusted for cognition. Spouses also report higher increases in FAQ scores over time compared to children, although this difference may be due to changes in cognitive ability as measured by the MMSE rather than bias.
Nanostructured lipid‐loaded nerolidol ameliorate cyclophosphamide‐induced neuronflammation and cognitive dysfunction
Authors: Iqubal Ashif , Syed Mansoor Ali , Najmi Abul Kalam , Ali Javed , Haque Syed Ehtaishamul
Published: December 2020

Background

Cyclophosphamide‐induced neurotoxic manifestations (neuronal oxidative stress, neuroinflammation, apoptosis and dementia) is major limitation for clinicians and reduce the quality of life of patients. However, to date, there are no approved adjuvant therapy available to attenuate these neurotoxic manifestations. Therefore, in the current study we explored the neuroprotective effect of nanostructured lipid loaded nerolidol nanoformulation, which is a naturally occurring lipophilic sesquiterpene having potent anti‐oxidant and anti‐inflammatory potential.

Method

Molecular docking study was performed to assertain the binding affinity of nerolidol with p65 subunit of NF‐kB. Nerolidol nanoformulation and nerolidol suspension were administered at the dose of 200 mg/kg, p.o for 14 days and neurotoxicity was induced in Swiss Albino mice by administrating a single dose of cyclophosphamide 200 mg/kg, i.p on 7th day. Forced Swim test, step down latency and Passive Avoidance test were formed. On 15th days animals were sacrificed, brain was removed and proceeded for the biochemical, histological and immunohistochemical study.

Result

Molecular docking study showed significant binding of nerolidol with NF‐kB. Neurobehavioural study showed significant cognitive derailment, biochemical study showed increased oxidative stress, nitrative stress and neuroinflammatory markers. Histopathological study revealed significant damage to CA1, CA2, CA3 regions of hippocampus and frontal cortex. Immunohistochemical study showed increased expression of p‐NF‐kB p65 and cleaved caspase‐3. These neurotoxic effects were reduced by administrating nerolidol nanoformulation at the dose of 200 mg/kg where as nerolidol suspension at the dose of 200 mg/kg was found to be ineffective.

Conclusion

The finding of the current study showed that cyclophosphamide induced significant neurotoxicity which was very well reversed by the nerolidol nanoformulation at the dose of 200 mg/kg. Nerolidol, thus, can be a future therapeutic molecule to counteract cyclophosphamide‐induced neuronal oxidative stress, neuroinflammation, apoptosis and dementia.
Genetic associations in Alzheimer’s disease: A systematic review and meta‐analysis
Authors: Hema Sree G.N.S , Marisse Lakshmi Prasanna , K Mamatha , Vithal Abhigjyna , Satish Kshreeraja S. , Rajalekshmi Saraswathy Ganesan , K. Radhika , Burri Raghunath R.
Published: December 2020

Background

Elucidation of genetic associations underlying Alzheimer’s Disease (AD) pathogenesis and progression is of prime importance in early diagnosis and drug discovery. Despite existence of innumerable studies to comprehend the genetic hallmarks of AD, inconsistencies amongst the studies in ascertaining specific genes involved in AD risk prompted this Systematic Review and Meta‐analysis.

Method

The review protocol was registered in Prospero (CRD42019127482). AD related Boolean search strategy was generated to retrieve case‐control studies evaluating genetic associations in AD patients from Pubmed/MEDLINE, Cochrane library, Proquest, Europe PMC, Grey literature, HuGE navigator, Latin American and Carribean Health Sciences literature published till March‐2019. Case‐control studies that defined AD diagnosis through standard diagnostic criteria were included. Preclinical and in‐silico studies were excluded. The shortlisted studies were critically appraised through New Castle Ottawa Scale (NOS) and Q‐Genie tool and the resultant data was extracted. Meta‐analysis was performed for Single Nucleotide Polymorphisms (SNPs) that were reported to be replicated in two different ethnicities by at‐least two studies through random effects model using Revman 5.3. Publication bias was assessed using Egger’s test, funnel plot, Begg and Mazumdar rank correlation test. Later, Interim Venice assessment and sensitivity analysis were executed to evaluate the credibility and versatility of the selected studies respectively.

Result

Among 352 285 studies retrieved, only 793 studies that met the eligibility criteria were critically appraised. This ultimately resulted in 118 studies for systematic review out of which, 23 SNPs corresponding to 15 genes were prioritized for meta‐analysis. The following SNPs were found to be significantly associated with AD risk: rs3865444 (CD33) (p = 0.04; I2 = 40%; OR [CI] = 0.88 [0.78‐0.99]), rs7561528 (BIN1) (p = 0.03; I2 = 46%; OR [CI] = 0.86 [0.76‐0.98]) and rs1801133 (MTHFR) (p = 0.007; I2 = 18%; OR [CI] = 0.73 [0.61‐0.88]). Interim Venice criteria revealed moderate credibility for seven SNPs and weak credibility for 16 SNPs. Further, sensitivity analysis confirmed the versatility of the selected studies.

Conclusion

Our findings acknowledged significant associations of three SNPs: rs3865444, rs7561528 and rs1801133 with Alzheimer’s risk. This evidence has to be replicated further to substantiate the role of aforesaid SNPs in AD.
Homocysteic acid in blood can detect mild cognitive impairment (MCI) and MCI due to Alzheimer disease (AD) pathological change
Authors: Hasegawa Tohru , Kosoku Yoshinori , Sano Yuka , Yoshida Hiroshi , Kudoh Chiaki , Tabira Takeshi
Published: December 2020

Background

Recent our findings present a new early diagnostic marker for mild cognitive impairment (MCI), a pre‐stage of Alzheimer’s disease (AD). It may be a causative substance of AD and a therapeutic target. In the treatment of AD, it is thought to be most effective to intervene at the earliest and mildest stages. So it is desirable to use a biomarker that can be detected by a minimally invasive, cost‐effect technique.

Method

The participants of our study were between 60 to 90 years. The data set consisted of 12 participants with AD, 12 with MCI, and 9 cognitively normal individuals as Negative Control (NC) (33 in total).The study was approved by the research ethics committee of Kudoh Chiaki Neurosurgery Clinic. In the study, we measured TNF‐α, cortisol and ACTH by ELISA, and measured HCA, tau and phosphorylated tau by CLEIA.

Result

We evaluated which items were useful as diagnostic markers for MCI and AD by Receiver Operating Characteristic (ROC) analysis. In ROC analyses, for distinguishing diagnostic markers between NC and MCI, the ROC curve of HCA showed very high areas under the ROC curves (AUC). When 0.116 μM of HCA is chosen as the cut‐off, the sensitivity is 91.7% and the specificity is 77.8 %. In our results, the item of HCA was the most useful as a diagnostic marker for MCI. In ROC analyses, in distinguishing diagnostic markers between MCI and AD, the ROC curve of tau and p‐tau showed a very high AUC. When 17.0 pg/mL of tau and 5.9 pg/mL of p‐tau are chosen as the cut‐off, the sensitivity is 83.3%, 91.7% and the specificity is 91.7%, 75.0%, respectively.

Conclusion

Our results suggested that plasma HCA level is useful as early diagnostic markers of AD. This is because measured values of HCA increase in the stage of MCI, and are thus useful as a diagnostic marker for MCI. On the other hand, our results suggested that plasma tau and p‐tau are useful diagnostic markers for confirming disease progression, because their measured values are linked to cognitive decline and, thus, they are useful as diagnostic markers for AD.
Effects of an SGLT2 inhibitor on cognition in diabetes involving amelioration of deep cortical cerebral blood flow autoregulation and pericyte function
Authors: Wang Shaoxun , Liu Yedan , Zhang Huawei , Guo Ya , Li Man , Gao Wenjun , Fang Xing , Shaffery James P. , Hosler Jonathan P. , Roman Richard J. , Fan Fan
Published: December 2020

Background

Diabetes mellitus (DM) is a leading risk factor for aging‐related dementia. We previously demonstrated that an SGLT2 inhibitor (SGLT2i) reversed the impaired myogenic response (MR) of the middle cerebral artery (MCA) and cerebral blood flow (CBF) autoregulation on the surface cortex, and improved cognition with an eight‐arm water maze in 18‐month old diabetic rats. The present study aims to investigate whether normalizing plasma glucose by inhibition of SGLT2 also ameliorate MR of parenchymal arteriole (PA) and CBF autoregulation in the deep cortex, and the role of pericyte in the regulation of CBF autoregulation and cognitive function in DM.

Method

Deep cortical CBF autoregulation was studied using laser Doppler flowmetry coupled with an implanted fiber‐optic probe. MR of PA was investigated using a pressure myography. The novel object recognition and open field tests were used to evaluate cognition. Mitochondrial‐derived superoxide production was detected by MitoSOX, and mitochondrial function was evaluated using Seahorse XFe24. Cell contraction was detected by a collagen gel‐based kit.

Result

Deep cortical CBF rose by 223.34 ± 28.11, 49.03 ± 12.62, 50.12 ± 0.89%, respectively, in diabetic, SGLT2i treated diabetic and non‐diabetic rats when blood pressure was increased from 100 to 180 mmHg. PA constricted in response to elevated transmural pressure in SGLT2i treated diabetic and non‐diabetic rats, whereas dilated in diabetic rats. The percentage of time spent in the novel object was 43.32 ± 8.04%, 71.94 ± 8.48%, 75.68 ± 3.33% respectively in diabetic, SGLT2i treated diabetic, and non‐diabetic rats. No significant differences in total travel distance and resting time were found between these rats. High glucose‐treated pericytes displayed elevated mitochondrial ROS, and decreased ATP production, and lower their contractile capabilities.

Conclusion

These results indicate that the SGLT2 Inhibitor reversed the impaired MR of the PA, CBF autoregulation in the deep cortex, and cognitive impairments in old DM, which may involve amelioration of hyperglycemia‐induced mitochondrial ROS production and ATP depletion in pericytes.
Targeting the BDNF/TrkB pathway for the treatment of amyloid beta 1‐40‒induced neurodegeneration: Focus on ocular manifestations of Alzheimer’s disease
Authors: Lazaldin Mohd Aizuddin Mohd , Iezhitsa Igor , Agarwal Renu , Agarwal Puneet , Bakar Nor Salmah , Ismail Nafeeza Mohd
Published: December 2020

Background

Amyloidosis‐related alterations, similar to those seen in the brain of patients with AD, occur in the retina of glaucoma patients. Decreasing level of brain‐derived neurotrophic factor (BDNF) is believed to be associated with neurotoxic effect of Aβ peptide. Hence, in this study we investigated (1) the effect of BDNF on retinal damage induced by Aβ1‐40 and (2) involvement of BDNF‐TrkB signalling in neuroprotection by BDNF against beta 1‐40‐induced retinal damage in Sprague Dawley rats.

Method

Rats were divided into 3 groups: group 1 received PBS via intravitreal injection, group 2 received intravitreal Aβ1‐40 (5 nmol) while group 3 received BDNF (1 µg) as co‐treatment with Aβ1‐40 via intravitreal injection. Fourteen days after injections, rats were euthanized and eyes were enucleated, fixed and processed for histopathological examination of retinal and optic nerve morphology using H&E and toluidine blue staining, while retinal cells apoptosis were detected using TUNEL assay immunostaining. Estimation of GSH, SOD, catalase and BDNF level in retina was done through ELISA method. Additionally, retinal target proteins (caspase‐3, TrkB and ERK) and their gene expression level were assessed by Western blot analysis and real‐time PCR, respectively.

Result

BDNF showed protective effect against Aβ1‐40‐induced retinal and optic nerve injury by preserving retinal and optic nerve morphology, lowering number of apoptotic cells, improving oxidative status and restoring BDNF level. Neuroprotective effect of BDNF correlated with number of survived retinal ganglion cells after Aβ1‐40 exposure. Assessment of visual function of rats using visual object recognition tests showed that BDNF improved difficulties for rats to recognise the visual cues after Aβ1‐40 exposure thus showing that visual function of rats was relatively preserved by treatment with BDNF. It was observed that treatment with BDNF abolishes Aβ1‐40‐induced increase in retinal expression of caspase‐3 and upregulates TrkB and ERK levels as it was shown by western blot analysis. BDNF also suppresses Aβ1‐40‐induced transcriptional activity of caspase‐3 and increases TrkB and ERK transcriptional activity in the regulation of apoptosis.

Conclusion

Treatment with BDNF prevents Aβ1‐40 induced retinal injury by inhibiting Aβ1‐40‐induced neuronal apoptosis via downregulation of caspase 3 and upregulation TrkB and ERK levels.
Causal pathway to analyze racial disparities in ADRD
Authors: Kim Yejin , Jiang Xiaoqian
Published: December 2020

Background

Health disparities in prevalence of Alzheimer’s disease and related dementia (ADRD) across different racial groups are mostly due to variations in socioeconomic status and comorbidity such as cardiovascular disease, diabetes, and obesity. We aim to investigate multifactorial influence of comorbidity to the ADRD risk for African Americans compared to Caucasian.

Method

From 106 million patients’ electronic medical records in Cerner Health Facts, we built paired and comparable cohorts of each racial group by matching age, observation window, cardiovascular diseases, diabetes, obesity, and head injury. We then derived causal graphs respectively using PC algorithms.

Result

We found that the two causal graphs from African‐American and its paired Caucasian show very different clinical pathway to ADRD, even though the two cohorts follow similar distribution except race. For African‐American, we found three inflammatory pathways and one cardiology pathway, whereas for paired Caucasian, we found a pathway from polyneuropathy to septicemia, and dementia.

Conclusion

Our study identified the root and pathway of comorbidity risk factors, which hopefully will reveal more information about the differential weights of known risk factors to patients of different race.
CSF levels of the BACE1 substrate Neuregulin1 correlate with cognition and synaptic biomarkers in Alzheimer’s disease
Authors: Mouton‐Liger Francois , Dumurgier Julien , Cognat Emmanuel , Hourregue Claire , Zetterberg Henrik , Vanderstichele Hugo Marcel , Vanmechelen Eugeen , Blennow Kaj , Paquet Claire , Hugon Jacques
Published: December 2020

Background

The presynaptic protein Neuregulin1 (Nrg1) is cleaved by BACE 1 like amyloid precursor protein (APP), can activate post‐synaptic ErbB4 receptors and has been linked to schizophrenia. The couple Nrg1/ErbB4 is neuroprotective, can trigger synaptogenesis and plasticity and increases the expression of NMDA and GABA receptors. In addition this couple can also induce neuroinflammation and can reduce memory formation. In Alzheimer’s disease (AD) Nrg1 accumulates in neuritic plaques. It is therefore difficult to determine if Nrg1 has beneficial and/or detrimental effects in AD. BACE 1 levels are increased in AD brains and CSF, but no study has assessed CSF Nrg1 levels in AD and MCI‐ AD patients.

Method

This is a retrospective study, including 172 patients suffering from AD dementias (56), MCI‐ AD (21), non‐AD MCI (32), non‐AD dementias (36) and neurological controls (27). All patients had neurological exams, MRI and neuropsychological evaluations. After written informed consent and using the ELISA method, the CSFs of all patients were evaluated for Aβ1‐42, Aβ1‐40, tau, ptau, BACE1, neurogranin, SNAP25, SNAP25 aa40, synaptotagmin and Nrg1.

Result

Levels of Nrg1 were significantly increased in the CSF of AD and MCI‐AD patients compared to non‐AD MCI, non‐AD dementias and neurological controls. In addition, Nrg1 levels positively correlated with tau, ptau, Aβ 1‐40, all synaptic biomarkers and BACE1 levels and negatively with MMSE and Frontal Battery ( BREF) scores.

Conclusion

APP and Nrg1 are both cleaved by BACE 1 at synaptic levels. Aβ toxicity induces synaptic degradation with increased CSF levels of synaptic biomarkers and Nrg1. Reduced brain Nrg1 levels may reduce neuroptotection. Nrg1 is a new biomarker reflecting BACE1 activity and Aβ‐ induced neurodegeneration and can be correlated with the cognitive status in MCI‐AD and AD patients.
Utilizing a mobile clinical trials unit: Lessons learned from the first three years
Authors: Smith Amanda G. , Rodrigo Kelly , Lowe Patricia , Andrade Melissa , Burnett Elisabeth , Vasquez‐Ramos Myriam , Mba Ijeoma , Janavs Juris , Major Beth , Epstein Patricia , Wynne‐Phillips Heather , Flynn Myrna DeJesus , Morgan Dave
Published: December 2020

Background

It is well‐established that clinical trials for Alzheimer's Disease need faster enrollment. Transportation challenges can sometimes prevent potential subjects from participating in clinical trials. In Florida, many persons live more than 30 minutes from sites conducting clinical trials. Based on these facts, we created a mobile clinical trials unit that launched in the 2nd half of 2016.

Method

We created a mobile clinical trial unit on which all trial screening activity other than imaging could be performed. It is a 53' trailer with 400 square feet of space and allows for all aspects of study visits other than imaging to be conducted on it. We reflected upon the successes and failures of the last three years of experience with the unit with the team members who staff it. We also documented feedback from sponsors and participants.

Result

We have previously reported that the mobile unit increased the number of minorities participating in memory screening at Health Fairs (CTAD 2016) and doubled the number of participants we screened in prevention trials (AAIC 2018.) Additional positive findings include increased visibility in the community, feelings from subjects that we were making an effort to accommodate them, increased request for appointments in our clinic, increased enrollment in treatment trials compared to our main clinic alone, and national and international interest in expanding the concept. Challenges included cost of moving the unit and need to use a trucking company to do so, space requirements for parking, unexpected maintenance issues and associated costs, hesitancy of sponsors to adopt the concept, need for development of unit‐specific SOPs, staffing issues, and additional work & accountability transporting study materials such as drug, source documents, and labs.

Conclusion

There are both pros and cons associated with the operation of a mobile clinical trials unit, especially when the unit itself is only semi‐mobile. Nevertheless, it has thus far ultimately been successful in expanding our pool of subjects across the spectrum of AD and increasing trial participation.
In silico modeling of pathogenic point mutations in APP, PSEN1 and PSEN2 in Asia
Authors: Nguyen Thuy Trang , Vo Tuong Kha , Vo Van Giau
Published: December 2020

Background

Alzheimer’s disease (AD), the most common form of senile dementia, is a genetically complex disorder. In most Asian countries, the population and the number of AD patients are growing rapidly, and the genetics of AD has been extensively studied. Amyloid protein precursor (APP), presenilin‐1 (PSEN1), and presenilin‐2 (PSEN2) mutations cause autosomal dominant forms of early‐onset Alzheimer disease (EOAD). Although these genes were identified in the last several decades, variant classification remains a challenge, highlighting the need to elucidate their role in neuropathologic features of autosomal dominant ADAD.

Method

We tested the performance of four prediction tools (Align‐GVGD, SIFT, PolyPhen‐2, MutationTaster2) using a set of 50 missense variants that had previously been reported. Finally, 3‐D modeling was also performed for all mutations.

Result

We summarized substitution mutations in the APP, PSEN1 and PSEN2 genes in Asia and attempted to identify pathogenic mutations using Align‐GVGD, SIFT, PolyPhen‐2, MutationTaster2, and 3‐D structure analysis techniques. Most of the mutations were confirmed as pathogenic mutations by these algorithms.

Conclusion

Our results contribute to a better understanding of the behavior of the mutations and their pathogenic nature process, which is necessary to understand AD pathogenesis. Following this work, some potential mutations would be chosen and further checked out their pathogenicity of in AD through cellular studies.
Anti‐amyloidogenic and cyclooxygenase inhibitory activity of Indigofera zollingeriana Miq
Authors: Vo Tuong Kha , Nguyen Thuy Trang , Vo Van Giau
Published: December 2020

Background

Alzheimer's disease (AD) is a devastative neurodegenerative disorder which needs adequate studies on effective treatment options. The extracts of plants and their effect on the amelioration of AD symptoms have been extensively studied. Indigofera zollingeriana Miq is known in traditional folk medicine for treating cough, cold, sore throat, fever, wounds, epilepsy, and headaches.

Method

To discover the scientific pharmacological potential of Indigofera zollingeriana Miq, we explore its anti‐inflammatory, cytotoxicity, and inhibition of amyloid‐beta (Aβ) aggregation effects.

Result

Cyclooxygenase assay of the ethanol and aqueous extracts of Indigofera zollingeriana Miq are more selective to COX‐1 inhibition with a 50% inhibitory concentration (IC50) of 10.15 μg/mL for the both extracts. Neuroblastoma SH‐SY5Y inhibition and thioflavin T assay amyloid‐beta (Aβ) aggregate inhibition of the extracts significantly revealed their potential therapeutic effects against Alzheimer’s disease. The putative compounds from the LC‐MS analysis could be responsible for the observed activities.

Conclusion

The results suggest that Indigofera zollingeriana Miq possesses anti‐inflammatory and anti‐neurodegenerative properties and a promising lead as a source of pharmacologically active compounds.
PET‐[18F]UCB‐H for assessing synaptic density in FTD
Authors: Salmon Eric , Bahri Mohamed Ali , Plenevaux Alain , Becker Guillaume , Seret Alain , Giacomelli Fabrice , Delhaye Emma , Degueldre Christian , Balteau Evelyne , Luxen André , Bastin Christine
Published: December 2020

Background

The behavioural variant of fronto‐temporal dementia (FTD) is characterized by clinical symptoms including behavioural and cognitive changes and by neurodegenerative involvement of the anterior part of the brain. The objective was to study the in vivo distribution of synaptic loss.

Method

12 patients with possible FTD and frontotemporal hypometabolism on FDG‐PET (mean disease duration of 4 years) were compared to 12 control participants and 12 patients with Alzheimer’s disease, matched for age, sex and education. Measures of verbal fluency, episodic memory and awareness of cognitive impairment did not differ between patients groups. We used [18F]UCBH‐PET to assess the regional loss of synaptic density. Total distribution volume was obtained with Logan method and carotid artery derived input function. SPM12 was used to analyze pve‐corrected PET and MRI images.

Result

A significant decrease of [18F]UCBH uptake was observed in the right anterior parahippocampal gyrus of FTD patients, while atrophy was observed in the ventromedial prefrontal cortex. Loss of synaptic density was observed in the right hippocampus of AD participants, while atrophy extended from the right hippocampus to bilateral posterior associative cortices. AD patients showed lower [18F]UCBH uptake in the precuneus that FTD patients. Anosognosia for clinical symptoms was correlated with synaptic density in caudate nucleus and prefrontal cortex in FTD, and with synaptic density in posterior hippocampus in AD.

Conclusion

Synaptic loss was predominant in the anterior parahippocampal gyrus of our bvFTD patients. This region is part of the limbic network and the perceptive social brain. A validated measure of anosognosia (a characteristic but variable symptom in bvFTD) was related to synaptic density in two interconnected regions, caudate nucleus and anteromedial prefrontal cortex, the later being involved in self‐reference.
Optimizing Practices, Use, Care and Services‐Antipsychotics (OPUS‐AP): A phase 2 scale‐up to 129 long‐term care (LTC) centers in Quebec, Canada
Authors: Bruneau Marie‐Andrée , Couturier Yves , Gilbert Suzanne , Boyer Diane , Ricard Jacques , MacDonald Tanya , Arcand Marcel , Morin Michèle , Tousignant Marilyn , Rhéaume Andrée‐Anne , Turcotte Jean‐Philippe , Cossette Benoit
Published: December 2020

Background

Antipsychotics are often used for the first‐line management of behavioral and psychological symptoms of dementia (BPSD) despite risks and side effects, and with disregard for guidelines recommendations to prioritize non‐pharmacological interventions. OPUS‐AP builds on Canadian Foundation for Healthcare Improvement, Appropriate Use of Antipsychotic initiatives and previous work by the 4 university‐affiliated research centers on an aging population in Quebec. The OPUS‐AP strategy is supported by an evidence‐based approach, involving provincial clinical guidelines developed by Québec’s health‐technology assessment agency, the Institut national d’excellence en santé et en services sociaux (INESSS). In phase 1 of OPUS‐AP, conducted in 24 long‐term care (LTC) centers in Quebec, Canada, antipsychotic deprescribing (cessation or dose decrease) was achieved in 85,5% of residents in whom it was attempted (Cossette et al. JAMDA, 2019).

Method

Phase 2 of OPUS‐AP was conducted in 129 LTC centres in Quebec, Canada, from April to December 2019. OPUS‐AP aims at improving resident care through increased staff’s knowledge and competency, resident‐centered approaches, nonpharmacologic interventions, and antipsychotic deprescribing in inappropriate indications. OPUS‐AP is implemented through integrated knowledge translation and mobilization activities. Antipsychotic, benzodiazepine, antidepressant prescriptions and BPSD were evaluated every 3 months for 6 months.

Result

At baseline, 10,601 residents were admitted on OPUS‐AP participating wards from which 74% had a diagnosis of major neurocognitive disorder (MNCD) and 47% an antipsychotic prescription. The follow‐up cohort included 4,087 residents with both MNCD and antipsychotic prescription. Among the 1216 residents in whom antipsychotic deprescribing was attempted between baseline and 6 months and still included at 6 months, successful deprescribing was achieved in 85.6% (cessation 50.0% or dose decrease 35.6%). No increase in benzodiazepine or antidepressant prescriptions nor worsening of BPSD were observed.

Conclusion

Phase 2 of OPUS‐AP confirmed phase 1 results of successful antipsychotic deprescribing with scale‐up to 129 LTC centers. Phase 3 of OPUS‐AP is underway in 2020 in all of Quebec’s 341 public LTC centers.
A conceptual framework for future studies on subtypes of Alzheimer's disease
Authors: Ferreira Daniel
Published: December 2020

Background

Alzheimer’s disease (AD) is a heterogeneous disease. Recent neuropathology and neuroimaging studies have sought to formalize this heterogeneity by defining AD subtypes based on the distribution of tau neurofibrillary tangle pathology and regional brain atrophy. These studies consistently revealed the existence of four subtypes: typical, limbic‐predominant, hippocampal‐sparing, and minimal atrophy AD. We will give an overview on the current state‐of‐the‐art, leveraging on the first systematic review and meta‐analysis on subtype studies based on neuropathological and neuroimaging data, recently published by our group (Ferreira et al. 2020 Neurology). We will also present a conceptual framework to guide subtype studies in the future. Our ultimate goal was to advance our current understanding of mechanisms driving heterogeneity in AD dementia and its pre‐dementia stages.

Method

The EMBASE, PubMed and Web of Science databases were consulted for AD subtype studies based on neuropathological or neuroimaging data. We calculated meta‐analytical estimates on key demographic, clinical, and CSF biomarker measures. Prevalence values for the subtypes were also calculated. We summarized and integrated all the data on a hypothetical conceptual framework.

Result

Our meta‐analytical analysis shows that typical AD displays tau neurofibrillary tangle pathology and atrophy both in hippocampus and association cortex, and has a pooled frequency of 55%. Limbic‐predominant, hippocampal‐sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between‐subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels.

Conclusion

We identified two core dimensions of heterogeneity: “typicality” and “severity”. We propose that these two dimensions determine individuals’ belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and comorbid non‐AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, results interpretation, and understanding mechanisms in future subtype studies. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease‐modifying drugs for AD.
Disentangling neurodegeneration subtypes of Alzheimer’s disease using data‐driven methods
Authors: Grothe Michel J. , Levin Fedor , Teipel Stefan J. , Habes Mohamad
Published: December 2020

Background

Research on understanding heterogeneity in Alzheimer’s disease (AD) has traditionally relied on ‘a priori’ categorizations of recognized clinical or pathologic disease variants. More recently, application of clustering methods to high‐dimensional spatial features from neuroimaging data has allowed data‐driven discovery of AD subtypes based on differentiated regional patterns of neurodegeneration.

Methods

We provide an up‐to‐date review of structural MRI studies that leveraged data‐driven approaches to examine heterogeneity in regional neurodegeneration patterns among AD patients. Findings will be discussed in relation to different families of clustering methods employed across studies. We further present primary data from our ongoing studies characterizing AD neurodegeneration subtypes by means of FDG‐PET as a potentially more sensitive molecular imaging marker of neurodegenerative processes.

Results

Data‐driven studies across multiple independent cohorts and employed methodologies provide converging evidence for the existence of distinct MRI atrophy subtypes that broadly resemble the differentiation into atypical medial temporal‐ vs neocortical‐predominant patterns characterizing established neuropathological subtypes. These studies not only allowed for a regionally more detailed characterization of the respective atrophy patterns, but also pointed to the existence of more differentiated atrophy profiles within these broad subtype categories. Concordantly, our cluster analyses of FDG‐PET data confirmed a broad distinction into AD subtypes characterized by medial temporal/limbic‐ vs neocortical‐predominant hypometabolism, and at a higher resolution further distinguished a rare frontal variant from the typical temporo‐parietal neocortical pattern (Fig‐1). In a pilot imaging‐pathologic association study based on ante‐mortem FDG‐PET of 34 pathologic AD cases, the neocortical‐predominant subtype was more likely to have neocortical tau Braak stage VI and to have higher CERAD ratings of cortical neuritic plaques, whereas Thal amyloid phase and diffuse plaque ratings did not differ from the limbic‐predominant subtype. The limbic‐predominant subtype had a higher burden of comorbid cerebrovascular disease, but TDP‐43 or Lewy body comorbidity did not differ significantly between subtypes.

Conclusions

Data‐driven approaches applied to neuroimaging data can give an unbiased and regionally detailed estimate of the distinct neurodegeneration subtypes present among AD dementia patients. Methodological consensus on the optimal clustering techniques and input features is needed to define the most robust subtype‐defining neurodegeneration patterns to be used for patient stratification.
Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics
Authors: Tijms Betty M. , Visser Pieter Jelle
Published: December 2020

Background

Alzheimer’s disease (AD) is a biologically heterogeneous disorder. Cerebrospinal fluid (CSF) contains thousands of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. Using a dual clustering technique, non‐negative matrix factorization, we studied whether biological subtypes of AD can be detected in CSF proteomics in two independent cohorts, and we will provide an overview how subtypes differed on biological clinical characteristics.

Method

We selected individuals with AD (defined as abnormal ab42 in CSF) and controls (normal cognition and normal AD biomarkers) from ADNI and the EMIF‐AD biomarker multimodality biomarker discovery study (ADNI: 32 preclinical AD, 103 prodromal AD, 62 AD‐dementia, 45 controls; EMIF‐AD: 56 preclinical AD, 90 prodromal AD, 77 AD‐dementia, and 82 controls). In ADNI we studied 149 proteins measured with mass reaction monitoring spectrometry and a multiplex rules based medicine assay, and in EMIF‐AD 556 proteins measured with tandem‐mass tag spectrometry. Proteins were selected when concentrations differed between AD and controls, scaled to include only positive values and then clustered with non‐negative matrix factorisation. Subtypes were compared on demographical, clinical and protein CSF markers not used for clustering.

Result

Both cohorts showed three protein profiles, based on which we allocated individuals to three subtypes: In EMIF‐AD, subtype 1 included 80 individuals (36%), subtype 2 included 71 individuals (32%) and subtype 3included 72 individuals (32%). In ADNI, subtype 1 included 97 individuals (45%), subtype 2 included 69 individuals (35%) and subtype 3 included 39 individuals (20%). Gene Ontology (GO) pathway analysis showed that proteins specifically increased in subtype 1 were enriched for synapse functioning, in subtype 2 for innate immune system activation and in subtype 3 for blood‐brain barrier dysfunction (all pFDR <0.05). Compared to controls, subtypes showed overlapping and distinct regional atrophy patterns: subtype 1 atrophy showed most pronounced atrophy in temporal areas; subtype 2 showed more involvement of parietal areas, and subtype 3 of frontal areas.

Conclusion

Biological heterogeneity amongst individuals with AD can be robustly detected with CSF proteomics, and this provides new opportunities for development of patient tailored treatment approaches.
DNA Aβ42 immunotherapy induces epigenetic changes of the gene expression profile in brain in the 3XTG‐AD mouse model
Authors: Lambracht‐Washington Doris , Fu Min , Rosenberg Roger N.
Published: December 2020

Background

Alzheimer's disease (AD) has been associated with deposition of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. We have used a DNA Aβ42 trimer construct for immunization of 3xTg‐AD mice and found significant reduction of amyloid and tau pathology. Our working hypothesis is that DNA Aβ42 immunotherapy affects the gene expression profiles in brains of the treated mice, and is thus changing the microenvironment for possible AD prevention.

Methods

Mice were immunized with DNA Aβ42 trimer in 6‐week intervals during the experimental time line (24 months). Amyloid and tau pathology was evaluated in brains by immunohistochemistry. FFPE sections from DNA Aβ42 immunized 3xTg‐AD mice, non‐treated 3xTg‐AD controls and age and gender matched wild‐type controls (n=4/group) were used for RNA isolation and gene expression analysis using a Neuroinflammation gene panel (Nanostring nCounter).

Results

The analysis of differently expressed genes in brains from 24 months old mice showed significant changes in transcript levels between non‐immunized AD mice and wild‐type controls for genes involved in microglia (Trem2, Ccl3, Ccl4, Csf1, CD68, CD84, Apoe, Itax1, Irf8, Ctse, Ctss) and astrocyte function (Lnc2, CD14, CD109, CD72, Vim, S100a10), cytokine and inflammatory signaling (Mpec1, Btk, Ssp1, Il1r1, Il6a, Inpp5d, Ch25h, Lilrb4a, Syk, Tgb1), matrix remodeling (Ptprc, Ssp1, Mmp2, Tgfb1), apoptosis (Bcl2a1, Bax, Casp4, Casp8, Fas), the innate (C1qa, C1qb, C3ar1, C4a, Btk, Tyrobp, Ly6a, Syk) and adaptive immune response (CD74, Btk, Ctse, Ctss, Fcer1g, Fcr2b, Inpp5d, Lilrb4a), consistent with an inflammatory phenotype in AD. These genes were also changed in the DNA Aβ42 immunized 3xTg‐AD mice compared to the non‐immunized AD mice nudging into direction of the wild‐type controls indicative of downregulation of inflammation due to immunotherapy, respectively. Significant changes were found for the immediate early genes, Bdnf, Arc, Homer1, Egr1 and c‐fos, involved in neuronal and neurotransmission pathways which were higher expressed in DNA Aβ42 immunized 3xTg‐AD mice and wild‐type controls compared to non‐immunized 3xTg‐AD mice indicating effects of DNA Aβ42 immunotherapy on synapse plasticity and memory formation.

Conclusion

The multitude of changes after DNA Aβ42 immunization shows that this intervention has high potential for disease prevention.
Novel modulators of mitochondrial complex I ROS production as potential AD therapeutics
Authors: Green Jakob , Jiang Yuqi , Chen Qun , Lesnefsky Edward , Zhang Shijun
Published: December 2020

Background

Among the indicated pathogenic factors of Alzheimer’s disease (AD), mitochondrial dysfunction has been recognized as an essential contributor, especially for the late onset AD (LOAD). That this observed dysfunction is the cause or consequences of other AD‐related injuries has been debated, results from both sides are in agreement that the roles of mitochondria in connection with other AD pathologies are convergent. This strongly advocates that targeting mitochondrial dysfunction represents a promising approach to develop more effective AD therapeutics.

Method

Chemical probes based on a novel lead structure that showed promising neuroprotective activities both in vitro and in vivo AD models were designed and synthesized to identify protein targets. Mouse brain mitochondria were purified from C57BL/6 mice and complex I was further isolated. OXPHOS studies were conducted in purified mitochondria upon treatment with our lead compound. Photo‐affinity labeling studies were conducted upon incubation of chemical probes with complex I. Colocalization was studied using neuronal MC65 cells and chemical probes.

Result

OXPHOS studies established that the lead compound only modulated the state 3 respiratory of pyruvate, the complex I substrate, but not succinate, the complex II substrate. Enzymatic studies of ETC also confirmed its selective modulation of complex I. The immunocytochemistry studies in MC65 cells indicated that the designed chemical probe localized to mitochondria. Protein labeling studies confirmed the direct interaction of the chemical probe with mitochondria complex I. Further analysis suggested that our chemical probe binds to the FMN binding site of complex I. Competition studies using the lead compound and NADH supported the selective labeling of complex I sub‐units.

Conclusion

Studies from in vitro, ex vivo, and in vivo models established that the lead compound selectively modulates the production of mitochondria complex I ROS without interfering with mitochondria membrane potential and bioenergetics, representing a novel mechanism of action. Chemical biology studies employing photo‐affinity labeling probes also confirmed the interaction of the probes with complex I and suggested the FMN binding site as the interaction site. Collectively, the results strongly encourage developing mitochondria complex I ROS modulators based on this novel chemical scaffold as potential AD therapeutics.
Mechanistic insights of novel NLRP3 inhibitors as potential AD therapeutics
Authors: Green Jakob , Blevins Hallie , Xu Yiming , Zhang Shijun
Published: December 2020

Background

NLRP3 inflammasome is an essential component of innate immunity and its activation leads to the production of interleukin (IL)‐1β and IL‐18, and promotes inflammatory cell death. Recent studies have indicated a critical role for the NLRP3 inflammasome in the pathogenesis of Alzheimer’s disease (AD), where neuroinflammation has been recognized as an essential player. Thus, novel NLRP3 inhibitors represent a novel approach to develop AD therapeutics.

Method

Chemical probes based on a novel lead NLRP3 inhibitor that exhibits promising neuroprotective activities in AD models were synthesized to understand mode of action. Recombinant human NLRP3 protein was produced with his‐tag attached on both N‐ and C‐terminus. Photo‐affinity labeling and pull‐down assays were conducted using cell lysates of J774A.1 cells, and analyzed by silver staining and western blotting. Binding studies were performed using the recombinant human NLRP3 protein by microscale thermophoresis (MST) technique. ATPase activity of NLRP3 protein was analyzed by ADP glow assay. Drug affinity responsive target stability (DARTS) studies were performed using J774A.1 cell lysates.

Result

Chemical probes exhibited comparable potency as the lead compound to inhibit the release of IL‐1β from J774A.1 cells. Protein labeling and pull‐down studies clearly indicated the selective recognition of NLRP3 protein from J774A.1 cell lysates by the chemical probe. Further competition studies revealed that our lead inhibitor bins to NLRP3 differently than MCC950, the known NLRP3 inhibitor. Binding studies also confirmed the direct interaction of our inhibitor with the NLRP3 protein. DARTS studies also showed that upon incubation with the lead inhibitor, the stability of NLRP3 by pronase digestion was increased. We also confirmed that our NLRP3 inhibitor does not inhibit the ATPase activity of NLRP3.

Conclusion

Chemical biology studies employing molecular biology, biochemical and biophysical techniques established that small molecule NLRP3 inhibitors derived from a novel chemical scaffold directly bind to the NLRP3 protein without interfering its ATPase activity, thus representing a novel mode of action. The results also indicated a distinct mode of action compared to the known NLRP3 inhibitor MCC950. Collectively, the results strongly encourage developing new analogs based on this novel chemical scaffold as novel NLRP3 inhibitors and potential AD therapeutics.
Mnemonic strategic training increases functional connectivity in amnestic mild cognitive impairment: Results from a randomized controlled trial
Authors: Simon Sharon Sanz , Hampstead Benjamin M , Silva Mariana PN , Duran Fabio LS , Fonseca Luciana Mascarenhas , Martin Maria Da Graça M , Avila Renata , Porto Fabio Henrique de Gobbi , Brucki Sonia Maria Dozzi , Martins Camila B , Tascone Lyssandra dos Santos , Amaro Edson , Busatto Geraldo , Bottino Cassio Machado de Campos
Published: December 2020

Background

Previous research showed that mnemonic strategy training (MST) improves cognitive performance in people with MCI, and has been associated with increased brain activation consonant with the cognitive processes engaged by the training, such as, semantic memory, decision‐making, cognitive control, face processing and social cognition. Despite the growing body of literature on MST in MCI, we are not aware of any randomized controlled study that have examined the effect of MST on resting‐state functional connectivity (FC). Therefore, the aim of the present study was to investigate the effect of MST, focused on face‐name associations, on resting‐state FC in older adults with MCI.

Method

Twenty‐six amnestic MCI participants were randomized to one of two interventions: MST (N=14) or an Education Program (EP) (N=12). Both interventions were face‐to‐face, and occurred twice a week over two consecutive weeks (i.e., four sessions). Open‐eyes resting‐state functional magnetic resonance imaging (fMRI) was collected at pre‐ and post‐intervention. Nine regions of interest (ROIs) were selected a priori, based on areas that showed activation changes in a face‐name fMRI paradigm after MST (considering the contrast post>pre within the MST group, and in the comparison MST > EP). Changes in FC (post > pre, and pre > post) were examined through ROI‐to‐ROI analysis in the contrasts MST > EP and EP > MST. Analyses were conducted with CONN toolbox 17.f, and significant results were corrected for multiple comparison using false discovery rate (FDR).

Result

At post‐intervention, the MST group showed increased FC relative to the EP. Specifically, there was FC increase between the right inferior frontal gyrus (pars triangularis) and three ROIs in the left hemisphere: fusiform gyrus, temporal pole and orbitofrontal cortex. Within group analysis showed that FC increased after intervention only in the MST group, whereas the EP group showed decreased FC.

Conclusion

Our findings indicate that MST enhance FC in functionally relevant regions for the training; effects that support a general change in the innate connectivity that are not limited to a task‐specific condition. Our results extent the knowledge on the underlying mechanisms of MST, and may provide neurophysiological evidence of transfer.