bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between carotid atherosclerosis and plasma Aβ levels in patients with high risk of stroke
Authors: Wang Anqi , Gao Ling , Wei Shan , Dang Liangjun , Shang Suhang , Chen Chen , Wang Jin , Huo Kang , Deng Meiying , Wang Jingyi , Qu Qiumin
Published: December 2020

Background

Growing evidence indicated that vascular factors contributed to the pathogenesis of Alzheimer’s disease (AD), but the relationship of atherosclerosis and AD is unclear. As Amyloid‐β (Aβ) deposition in the brain is a main pathophysiology of AD and plasma Aβ is closely related to Aβ deposition in the brain. In present study, we investigated the relationship between carotid atherosclerosis and plasma Aβ levels.

Method

Patients with high risk of stroke were from community stroke screening in Qubao Village, Xi'an. Carotid ultrasound was used to detect carotid atherosclerosis. Venous blood was collected on an empty stomach in the morning. Plasma Aβ1‐40 and Aβ1‐42 levels were measured by ELISA. Univariate and multivariate analysis were used to investigated carotid atherosclerosis and plasma Aβ1‐40 and Aβ1‐42 levels.

Result

Among 222 participants underwent carotid ultrasound, 149 had carotid atherosclerosis (49.01%). Univariate analysis showed that plasma Aβ1‐40 level and Aβ1‐42 level had no significant differences between carotid atherosclerosis group and non‐carotid atherosclerosis group (53.15 ± 8.77 vs. 50.96 ± 8.79 pg/ml, P=0.083; 41.07 ± 6.51 vs. 39.95 ± 5.93 pg/ml, P=0.217). Multivariate linear regression analysis showed that plasma Aβ1‐40 (b=1.832, p = 0.213), plasma Aβ1‐42 (b=1.605, P=0.131) and plasma Aβ1‐40/Aβ1‐42 ratio (b=‐0.012, P = 0.829) had no significant difference between two groups in the total population. However, in the non‐hypertensive population, plasma Aβ1‐40 and Aβ1‐42 were significantly higher in the carotid atherosclerosis group than those in the non‐carotid atherosclerosis group (b=6.774, 95% CI: 2.691‐10.858 pg/ml, P =0.001; b=3.408, 95% CI: 0.309‐6.508 pg/ml, P=0.032).

Conclusion

Among patients with high risk of stroke, carotid atherosclerosis was associated with higher plasma Aβ levels in non‐hypertension group. These indicated that atherosclerosis may be related to AD, and the relationships may be confounded by hypertension.
Disease progression and costs at two‐year follow‐up of GERAS‐US: A three‐year study of mild cognitive impairment and mild dementia due to Alzheimer’s disease in the United States
Authors: Chandler Julie , Zagar Anthony , Kim Yongin , Zimmer Jennifer A , Rentz Dorene M , Schwartz Ronald L , Fillit Howard M
Published: December 2020

Background

GERAS‐US is a 36‐month study that aims to understand long‐term clinical and economic outcomes of Alzheimer’s disease (AD). Changes in total costs at 1 and 2 years post‐baseline in beta‐amyloid‐positive [+] patients with mild cognitive impairment (MCI) and mild dementia (MILD) are reported.

Methods

Patients aged 55 to 85 years (N=617) were enrolled from 30 October 2016 through 09 October 2017. Mean 30‐day total societal costs (direct and indirect using opportunity costs [Figure 1]) were captured. Opportunity cost sums lost productive hours multiplied by national average annual gross hourly wage for workers and by lost leisure time for nonworkers (35% of hourly wage for workers). Costs are presented as mean (95% confidence interval [CI]) at baseline and at 1 and 2 years for the overall population and stratified by baseline severity (MCI vs MILD). Mean (95% CI) changes from baseline at 1 and 2 years are presented. A repeated measures model was used. Comparisons were conducted at 5% significance level.

Results

At baseline, patient mean age was 70.3 years for MCI and 71.7 years for MILD; overall, 52.7% were females. Analyses at 1 and 2 years post‐baseline included 483 (78.3%) and 388 (62.9%) patients, respectively. For amyloid[+] patients, mean change from baseline in Cognitive Function Index (study partner version) and Mini‐Mental State Examination scores demonstrated worsening at 1 and 2 years (Table 1). Mean estimated total societal costs for overall population decreased at 1 ($2343; p<0.001) and 2 years ($2641; p=0.026) vs baseline ($3033). Neither direct medical nor direct nonmedical costs changed over the 2‐year period for MILD patients, but direct medical costs increased significantly at Year 2 vs Year 1 for MCI patients (p=0.024; Table 2). Direct costs for study partners did not change over a 2‐year period; however, indirect costs were significantly higher for MILD vs MCI cohort at Years 1 and 2 (p£0.001).

Conclusions

Both function and cognition declined over 2‐year period for AD patients. In amyloid[+] MCI AD patients, direct medical costs increased from Year 1 to Year 2. Understanding why costs did not increase for MILD AD patients, despite clinical progression, requires further study.
The attitudes of physicians and the general public toward prognostic disclosure of different serious illnesses: A nationwide survey
Authors: Oh Sinae , Yun Young Ho , Kim Young Ae , Kim Yu Jung , Shim Hyun‐Jeong , Song Eun‐Kee , Kang Jung Hun , Kwon Jung Hye , Lee Jung Lim , Lee Soon Nam , Maeng Chi Hoon , Kang Eun Joo , Do Young Rok , Yun Hwan‐Jung , Jung Kyung Hae
Published: December 2020

Background

Although international guidelines recommend palliative care approaches for many serious illnesses, the palliative needs of patients with serious illnesses other than cancer are often unmet, mainly due to insufficient prognosis‐related discussion. We investigated physicians’ and the general public’s respective attitudes toward prognostic disclosure for several serious illnesses.

Method

We conducted a survey of 928 physicians, sourced from 12 hospitals and the Korean Medical Association, and 1005 members of the general public, sourced from 17 major cities and provinces.

Result

For most illnesses, most physicians (adjusted proportions – end‐organ failure: 99.0%; incurable genetic or neurologic disease: 98.5%; acquired immune deficiency syndrome: 98.4%; stroke or Parkinson’s disease: 96.0%; and dementia: 89.6%) and members of the general public (end‐organ failure: 92.0%; incurable genetic or neurologic disease: 92.5%; acquired immune deficiency syndrome: 91.5%; stroke or Parkinson’s disease: 92.1%; and dementia: 86.9%) wanted to be informed if they had a terminal prognosis. For physicians and the general public, the primary factor to consider when disclosing terminal status was “the patient’s right to know his/her condition” (31.0%). Meanwhile, for the general public the main reason for not disclosing prognosis was “psychological burden such as anxiety and depression” (35.8%), while for the physicians it was “disclosure would have no beneficial effect” (42.4%).

Conclusion

Physicians and the general public strongly agree that disclosure of a terminal prognosis respects patient autonomy in several serious illnesses.
Clinical development of tricaprilin, a ketogenic drug for Alzheimer's disease
Authors: Walker Judith Anne , Nelleman Lars , Henderson Samuel T , Morimoto Bruce
Published: December 2020

Background

Cerebral glucose hypometabolism in posterior cingulate, parietal, temporal, and prefrontal cortex is an early feature of Alzheimer’s disease (AD). Cells in these regions which exhibit a defect in glucose metabolism have been shown to preserve the ability to metabolise ketones. We report on an approach to induce ketosis and treat AD with a new drug formulation of a semi‐synthetic triglyceride, tricaprilin.

Method

Novel formulations of tricaprilin were developed and tested in vitro, in vivo, and in human studies to assess pharmacokinetics, safety, and tolerability. The clinical studies were conducted in healthy human Caucasian and Asian volunteers and in a variety of food conditions.

Result

Two new formulations of tricaprilin showed desirable PK characteristics, leading to generation of ketones and excellent safety and tolerability, when administered in doses of 20g after a meal, in both Caucasians and Asians.

Conclusion

The selected formulation will be moved forward in drug development with an ascending dose study in healthy elderly subjects and a Phase 3 study in mild to moderate Alzheimer's disease.
Nutritional status is associated with cognitive function among the elderly at hospital admission in Southwest China
Authors: Wuhan Yu , Lü Yang
Published: December 2020

Background

The evidence regarding the effect of nutritional status in aging and cognitive impairment has not been proved yet although the effects of malnutrition on progression in AD and dementia is becoming established.

Method

2365 participants aged 60 years or above were recruited from January 2013 to September 2019. They were divided into three age groups: young older (60–69 years), middle older (70–79 years), and old older (≥80 years). Nutrition status was analyzed via the Mini Nutritional Assessment Short Form (MNA‐SF). Global cognitive function was assessed with the Mini Mental State Examination (MMSE). Nutrition‐associated factors were analyzed, including Barthel Index (BI), Body mass index (BMI), social factors (education status, marital status).

Result

The mean age was 76.24±7.91 years and 45.9% were males. 33.45% were identified as malnutrition risk and 5.54% malnourished. In the old older group (≥80 years), 48.63% were malnutrition or at risk for malnutrition and 53.65% have cognitive impairment. In middle older group (60–69 years), 31.79% were at risk of malnutrition and 4.62% were malnourished, while 32.24% of them had impaired cognitive function. However, prevalence of malnutrition and at risk for malnutrition was 3.49% and 25.25% in young older group (60–69 years), respectively; moreover, only 18.77% of participants have cognitive impairment. MNA‐SF score was positively correlated with MMSE score (R= 0.392, P < 0.0001) and BI (R=0.398, P< 0.0001) in old older group. Participants who were at risk of malnutrition or malnourished had significantly poorer performance in the cognitive test (P < 0.001) in comparison to those who were well nourished. In particular, the association of the orientation (R= 0.381, P < 0.0001) and the language (R= 0.302, P < 0.0001) with nutritional status were most pronounced in old older group.

Conclusion

The prevalence of malnutrition and cognitive impairment increases with age, especially in patients over 80 years old. Malnutrition is associated with cognitive impairment. There was also a moderate correlation between nutritional status and cognition domain including orientation and language. The implication of this is the possibility that malnutrition is an important driving factor of cognitive decline. Thus, patients with cognition impairment should pay more attention to nutritional status.
Determinants of subjective cognitive decline in dementia‐free older adults: A population‐based study
Authors: Zullo Leonardo , Clark Christopher , Popp Julius ,   CoLaus/PsyCoLaus Investigators
Published: December 2020

Background

Subjective cognitive decline (SCD) is common in older adults and may represent the earliest clinical manifestation of cognitive decline evolving to dementia. Still little is known about factors related to SCD.

Method

We conducted a cross‐sectional analysis on 1567 community‐dwelling, dementia‐free participants aged 64 years and older from CoLaus/PsyCoLaus, a population‐based study from an urban area in Switzerland. SCD was assessed using a validated 10‐item questionnaire. Quality of life, socioeconomic status, depression, personality, professional activity, and perceived social support were measured, and a comprehensive neuropsychological test battery was administered. Multivariate regression models were used to explore the data. Furthermore, we investigated whether SCD predicts cognitive decline in a subgroup with available longitudinal data.

Result

Mean age was 70.9 ± 4.7 and SCD was present in 18.5%. Younger age, higher socioeconomic status, neuroticism, depression, and their interaction as well as poorer performance in memory and verbal fluency tasks were associated with SCD. Exploratory analysis revealed associations between SCD and interaction of neuroticism with quality of life. Two items from the SCD questionnaire predicted cognitive decline five years later in a subgroup with mild cognitive impairment at baseline.

Conclusion

Besides cognitive performance, specific psychosocial factors are associated with SCD in dementia‐free older people. These findings suggest possible intervention targets to reduce cognitive complaints and prevent cognitive decline.
Quality of life and quality of care: A pilot mobile app to promote the psychosocial well‐being of informal caregivers of older adults with Alzheimer's disease and related dementias
Authors: Lee Kathy , Jaworski Justyn ,   UTA Bioengineering Department Senior Design Research Team (Tanzim Choudhury, Debbie Vang & Kristen Duke)
Published: December 2020

Background

An increasing number of people with Alzheimer’s disease and related dementias (ADRD) live in their own homes with intensive assistance from informal caregivers (e.g., family or friends). Progressive symptoms of ADRD can affect the quality of life of the caregivers as well as people with ADRD. Mobile technology shows great potential to fill this gap with its accessibility, affordability, and repository for information. The purpose of this study was to develop a pilot mobile app (QLQC Tracker) that helps caregivers track and review their psychosocial well‐being and to test its reliability and usability.

Method

Our methodology in developing QLQC Tracker leverages existing Google cloud data services for logging of encrypted data. The Android Studio development environment was utilized for designing, building, and testing the app while Matlab was utilized for decryption, parsing of data, and development of the multilayer perceptron to process the data received from the app. The app entails four categories: mental health, social activities, frequently asked questions, and helpline information. The app informs the caregivers with trends in their overall psychosocial well‐being on a weekly basis. College students were invited to test the reliability and usability of the app (N=45). Questions were asked using the USE (Usefulness, Satisfaction, and Ease of use) questionnaire (Gao, Kortum, & Oswald, 2018).

Result

First, each participant was asked to enter data and click each tab up to 10 times. In total, the app was run 310 times and the reported crash rate was 0.84%. The overall satisfaction score of the app was 6.07 (SD=1.23; range 1‐9). Lastly, the mean value of the usability score of the app was 6.22 (SD=1.15; range 1‐9). The students aged between 20‐49 (n=27) scored 6.04 (SD=1.34) and the students aged 50+ (n=18) scored 6.50 (SD=0.71) for the usability of the app.

Conclusion

QLQC Tracker helps informal caregivers understand their psychosocial well‐being by tracking their perceived burdens and levels of social activities. Effective care planning for people with ADRD should include informal caregivers, and the cumulative well‐being data of the caregivers will support the care planning process.
Cerebrovascular reserve differentiates cognitively normal older adults from individuals with mild cognitive impairment
Authors: Rane Swati , Grabowski Thomas J
Published: December 2020

Background

Abnormal cerebral blood flow (CBF) is observed in early Alzheimer’s disease. Cerebrovascular reserve (CVR) represents the ability of the vasculature to maintain normal CBF. While CBF abnormalities can indicate a primary vascular dysfunction, it could also arise secondary to neurodegeneration and reduced metabolic demands. CVR, on the other hand, is a specific marker of vascular insufficiency. Our goal was to evaluate the associations between CVR, CBF, and cognition in older adults with and without MCI.

Methods

70 older adults (>65 years 77.3 ± 8.32 years old, 42F, 46 controls i.e., NC and 24 MCI) were scanned in compliance with Institutional Review Board guidelines. Besides a T1 scan, we performed pCASL to quantify baseline CBF and a breath‐hold BOLD fMRI experiment to quantify CVR. We use a mixed‐effects model in FSL to test CVR and CBF differences between groups as well as association with cognitive tests, i.e., Montreal Cognitive Assessment (MoCA), Immediate and Delayed recall (CRAFTi/d) and Trails‐B, using Gaussian random field theory for a cluster‐wise threshold of p = 0.05. All comparisons were adjusted for age and gender.

Results

Only CVR was significantly (p<0.05) different between NC and MCI (Figure 1). While there was no group difference in CBF, the group difference between CVR was no longer significant when adjusted for baseline CBF. Investigating further, high CBF was significantly associated with lower CVR in the MCI group only. A high CBF was very weakly related to high CVR in NC (Figure 2). A high CVR was associated with a high MoCA score (Figure 3) and CRAFTi/d (Figure 4).

Conclusion

We demonstrated the utility of a simple breath‐hold based CVR measurement in understanding the association between vascular mechanisms and cognition. It is likely that CBF is not different between groups because MCI participants utilize their vascular reserve to maintain baseline CBF. Consequently, an additional vascular challenge results in a lower CVR measurement. Furthermore, a higher CVR in MCI subjects such as that seen in association with cognitive tests could be a result steal phenomenon to redirect perfusion from degenerating tissue to viable tissue. However, these mechanisms need to be further investigated.
The BPSDPLUS Program: Efficacy of a novel person‐centred care approach to reduce neuropsychiatric symptoms in residents with dementia
Authors: Mortby Moyra E. , Sargent‐Cox Kerry , Beattie Elizabeth , Lautenschlager Nicola T. , Doyle Colleen , Anstey Kaarin J.
Published: December 2020

Background

The availability of effective non‐pharmacological interventions to ameliorate discomfort of residents with neuropsychiatric symptoms (NPS) living in aged care remains a pressing sector need. The BPSDPLUS Program is a novel person‐centred care training and intervention program developed by the team to provide aged care staff with a structured approach to identify and manage NPS using non‐pharmacological interventions. This pilot and feasibility study evaluates the efficacy of the BPSDPLUS Program to reduce NPS amongst residents over 12 months.

Method

77 residents (67% female; age range 67‐101) and 69 staff (79% female; age range 19‐63 years) from 3 sites of a non‐for‐profit care provider (includes dementia‐specific units) participated in the program. The Program’s unique “Buddy System” pairs each resident with a staff member who is responsible for completing all aspects of the program with/for their resident. Program components include a two day face‐to‐face staff training, monthly resident assessments and 15‐minute intervention sessions 3‐times a week using one of five non‐pharmacological interventions (meaningful and pleasant activities; reminiscence; music; gentle exercise; massage and touch). Primary outcome was reduction in NPS over time as measured by the Neuropsychiatric Inventory – Nursing Home (NPI‐NH) and assessed using mixed model estimates.

Result

Implementation of the BPSDPLUS Program over 12 months resulted in a significant reduction of NPI‐NH total scores over 12 months (β=‐1.07, 95% CI=‐1.62, ‐0.52), with a significant quadratic fixed effect (β=0.05, 95% CI=0.01, 0.09) indicating that the decline in scores slowed over the course of the trial. Similarly, significant fixed linear and quadratic effects were found in the unadjusted models for depression (linear β=‐0.77, 95% CI=‐1.35,‐1.20; quadratic β=0.05, 95% CI=0.01, 0.01), and apathy (linear β=‐0.84, 95% CI=‐1.33,‐0.35; quadratic β=0.05, 95% CI=0.01, 0.09). Further, irritability symptoms showed a significant decline across the trial (β=‐0.74, 95% CI=‐1.32, ‐0.16).

Conclusion

This pilot and feasibility study demonstrates the efficacy of the novel BPSDPLUS Program to significantly reduce NPS in residents living in aged care. Evidence‐based training and interventions programs such as the BPSDPLUS Program provide staff with improved skills and knowledge to improve the quality of person‐cantered care provided and manage the clinical consequences of NPS in dementia care.
Potential therapeutic agents from Philippine medicinal plants against Alzheimer's disease
Authors: Tan Mario A , An Seong Soo
Published: December 2020

Background

Natural products derived from plants have been in the lead of extensive studies in the search of potential anti‐Alzheimer’s disease agents. These plant species comprised a high chemical diversity of compounds. Natural products and plant extracts as therapeutic agents for AD have demonstrated that they favor neuroprotection against amyloid‐beta cytotoxicity and aggregation. Hence, the identification of plants and their bioactive constituents as a possible source of pharmacologically‐relevant compounds against AD is warranted.

Method

A total of 25 Philippine plant extracts were used in the experiment. The cytotoxicity of the extracts was initially determined using the ATP cytotoxicity assay utilizing the SH‐SY5Y and HEK‐293 cell lines. The non‐toxic extracts were subjected to our in‐house multimer detection system (MDS) assay. The procedure utilized three mutant cells, namely, Amyloid Precursor Protein (APP) 669, APP 604, and Presenilin 1 (PSE1 232). ELISA was used to establish whether the extracts and compounds have down‐regulated the aggregation of amyloid‐beta in the mutant cells against a positive control (phenol red) and a negative control (no treatment of cells), and in comparison with the normal HEK‐293 cells.

Result

Several plant extracts prevented the oligomer aggregation of amyloid‐beta in the mutant cells. These include Pandanus amaryllifolius, Pandanus simplex, Pandanus tectorius, Guettarda speciosa, Lasianthus trichophlebus, and Psydrax puberula. The prevention of oligomer aggregation is statistically different from the negative control. Also, these extracts were non‐toxic to the SH‐SY5Y and HEK‐293 cells. These results suggest that these plants may be developed as potential nutraceuticals to minimize the effects of AD. Currently, we are in the process of identification the bioactive compounds from these plant extracts using chromatographic and spectroscopic techniques.

Conclusion

The results in this study can pave the way for the development of new drugs with therapeutic value against AD. These drugs can also be candidates for pre‐clinical and clinical trials and licensing. The compounds can be used as chemical markers for the standardization of health products formulated from these plants. The scientific community including scientists, researchers and students can benefit from the new knowledge and discoveries and the validated protocols for the detection of extracts and compounds against AD.
Association between interhemispheric functional connectivity (IFC) and amyloid deposition in patients with different types of dementia
Authors: Cheung Eva YW , Mak Henry
Published: December 2020

Background

Previous studies have demonstrated that accumulations of amyloid fibrils (AF) altered the cognitive performance in patients suffered from Alzheimer’s disease (AD) and Mild cognitive impairment (MCI).

Method

85 participants (25 healthy controls HC, 16 AD, 21 MCI, 10 Mixed dementia (MD), 13 vascular dementia (VD) )were recruited to undergo Resting state functional MRI (rs‐fMRI) scanning and 18F‐Flutemetamol Positron Emission Tompography Computed Tomography (PETCT) scanning. Voxel Mirrored Homotopic Connectivity (VMHC) was calculated based on the method used by Kelly et al 2011 [1] and Zuo et al 2010 [2]. Standardized uptake value (SUV) were recorded from the PET images. With reference to the SUV of pons, SUV ratio (SUVR) were obtained. Association between IFC and SUVR were calculated based on the Spearman’s correlation test.

Result

IFC was negatively associated with SUV in AD at lingual gyrus (r=‐0.552, p=0.027) and cuneus (r=‐0.609, p=0.012) within visual network, VN; and MCI in Inferior frontal gyrus (IFG) triangular (r=‐0.488, p=0.02) within default mode network (DMN). For MD, IFC was positively associated with SUVR at angular gyrus (r=0.662 ,p =0.037), middle frontal gyrus (r=0.817 ,p =0.004), superior frontal gyrus (r=0.669 ,p =0.035) within DMN; at middle temporal gyrus MTG (r=0.554 ,p =0.049), Middle frontal gyrus orbital (r=0.742, p =0.014) within central executive network (CEN); at supplementary motor area, SMA (r=0.654 ,p =0.040) within sensory motor network (SMN); at IFG orbital (r=0.856 ,p =0.002) within dorsal attention network (DAN). For VD, IFC was positively associated with SUVR at posterior cingulate (r=0.611, p =0.026) within DMN; at middle temporal gyrus (r=0.563 ,p =0.045), rolandic operator (r=0.603 ,p =0.029), Precentral Gyrus (r=0.554 ,p =0.049) and Posterior central gyrus (r=0.653 ,p =0.019) within CEN; inferior temporal gyrus (r=0.605 ,p =0.028) within DAN.

Conclusion

The findings demonstrated the accumulation of AF decreases IFC in VN for AD and SRN for MCI. While for MD and VD, accumulation of AF increases with the IFC in DMN, CEN, SMN and DAN, suggesting that there is compensation of brain function, through recruiting other networks for non‐amyloid dominant dementia.
Neurotensin agonist alleviates metabolic disturbance, neuropathology, and cognitive decline in high‐fat diet–induced obese rats
Authors: Saiyasit Napatsorn , Chunchai Titikorn , Apaijai Nattayaporn , Pratchayasakul Wasana , Sripetchwandee Jirapas , Chattipakorn Nipon , Chattipakorn Siriporn C.
Published: December 2020

Background

Previous studies demonstrated that chronic high‐fat diet (HFD) consumption caused the development of obesity with metabolic disturbance, systemic inflammation, neuropathologies, including cognitive impairment and the disruption of brain neurotensin (NT) signaling. Moreover, exogenous NT treatment showed the neuroprotective effects and improved cognitive function in genetic‐induced obese models. However, the effect of NT agnoist on peripheral/brain pathologies following long‐term HFD consumption has not been investigated. The present study hypothesizes that NT agonist alleviates the aforementioned adverse effects in both periphery and brain in HFD‐fed rats.

Method

Male Wistar rats were received either a normal diet (ND) or HFD for 16 weeks. At week 13, ND‐fed rats were received the saline solution as a vehicle group (n=4‐6). HFD‐fed rats were randomly divided into 2 subgroups to receive either a vehicle or 1 mg/kg of PD149163 (NT agonist) via subcutaneous injection consecutively for 2 weeks (n=4‐6/group). At week 15, Morris water maze (MWM) test, and blood collection were performed, then animals were sacrificed. The metabolic parameters and peripheral inflammation were examined. Reactive oxygen species (ROS) production, dendritic spine density, number of microglia, and Alzheimer’s‐related protein expression in hippocampus were also determined.

Result

16‐week HFD‐fed rats developed obesity with peripheral insulin insensitivity, and increased level of serum lipopolysaccharide (LPS). Furthermore, a cognitive decline as demonstrated by the increased time to reach the platform and decreased time spent in the target quadrant from the MWM test (Figure 1A), increased number of Iba1+ cells (Figure 1B), elevated the levels of hippocampal ROS (Figure 1C), and increased the expression of p‐TauThr181 protein (Figure 1D), as well as reduced dendritic spine density were observed when compared to ND‐fed rats. Interestingly, the administration of NT agonist restores the aforementioned negative parameters in both periphery and brain in HFD‐fed rats (Figure 1A‐D).

Conclusion

These findings suggest that the administration of NT agonist alleviates peripheral pathologies and exerts neuroprotective effects by decreasing the expression of Alzheimer’s‐related protein, reducing brain inflammation/oxidative stress, and restoring cognitive function in obese insulin‐resistant rats. Therefore, NT should be a therapeutic target to prevent cognitive impairment in obese people.
Optimization of in vitro gene delivery to neurons containing an APP gene with a mutation responsible for familial Alzheimer’s disease for the development of a base editing therapy
Authors: Tremblay Jacques P. , Guyon Antoine , Joël Rousseau P.
Published: December 2020

Background

The Amyloïd Precursor Protein (APP) is preferentially cut by the α‐secretase enzyme in healthy individuals. However, an abnormal cleavage by β‐secretase leads to the accumulation of β‐amyloid peptides. Numerous APP genetic mutations cause Familial Alzheimer Disease (FAD). However, a rare APP gene variant (A673T) found in Icelanders drastically reduces cleavage by the β‐secretase. We hypothesized that the insertion of this A673T mutation in a patient’s genome using the CRISPR/Cas9 Base‐Editing Technology (Komor et al. Nature 2016) could be an effective method to slow down the progression of familial and sporadic forms of Alzheimer’s disease. The objective of this study is to eventually compare the efficiency by which a lentiviral or a dual‐AAV‐based vector could deliver a base‐editing complex (SpCas9VQR‐Target‐AID) into neurons in vitro.

Method

Neurons were obtained using two methods. The first method involved differentiating fibroblasts from a FAD patient or a mouse model with a London (V717I) mutation into neurons (Shrigley et al. JoVE 2018) (Figure 1), while the second method involved isolating hippocampal neurons from prenatal NL/F/G mice (Seibenhener et al. JoVE 2012). The dual AAV complex was designed to deliver two parts of the base editor gene separated by inteins (Villiger et al. Nat Med 2018). Hippocampal or induced neurons were transduced with lentivirus or AAV1. Cas9 detection was performed by immunofluorescence and Western Blot. The β‐amyloid peptides in supernatant were characterized and quantified by Meso Scale Discovery’s Aβ kit.

Result

We have been able to detect the Cas9 protein in neurons by western blot and immunofluorescence (Figure 2). In subsequent experiments, we will determine which delivery method will reduce more the β‐amyloid peptide.

Conclusion

Our approach aims to confirm the protective effect of the A673T mutation against the development of familial and sporadic forms of Alzheimer’s disease as well as develop an efficient delivery method for the base editing complex which will lead to an in vivo application. Long‐term perspective: We aim to develop a completely new therapeutic approach for AD and FAD using base editing or the new PRIME editing technique (Anzalone et al. Nature 2019). This may eventually lead to a Phase I clinical trial.
Antihypertensive medication classes and the risk of dementia: A systematic review and network meta‐analysis
Authors: GHE den Brok Melina , van Dalen Jan Willem , Abdulrahman Hanna , van Middelaar Tessa , van Gool Willem A , van Charante Eric P Moll , Richard Edo
Published: December 2020

Background

Hypertension is an important risk factor for dementia. Specific antihypertensive medication (AHM) classes may lower dementia risk more effectively than others. We aim to systematically review and synthesize the evidence on differential associations between AHM classes and the risk of dementia, using network meta‐analysis.

Method

Embase, MEDLINE and the Cochrane library were searched from origin to December 2019. We included randomized controlled trials and prospective cohort studies, including non‐demented participants with ≥one year of follow‐up. Data were extracted following PRISMA guidelines. Data on individual AHM classes were pooled using random effects frequentist network meta‐analysis.

Result

Fifteen observational studies and seven RCTs were included. Dementia occurred in 19,600/649,790 (3.02%) individuals. In observational studies, treatment with calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs) conveyed lower dementia risks than treatment with other antihypertensives: CCBs compared to ACE‐inhibitors (HR=0.84, 95%CI 0.74‐0.95), beta blockers (BB) (HR=0.83, 95%CI 0.73‐0.95) and diuretics (HR=0.89, 95%CI 0.78‐1.01); ARBs compared to ACE‐inhibitors (HR=0.88, 95%CI 0.81‐0.97), BB (HR=0.87, 95%CI 0.77‐0.99) and diuretics (HR=0.93, 95%CI 0.83‐1.05). There were too few RCTs to create a robust network based on randomized data but similar conclusions were suggested.

Conclusion

Recommending CCBs or ARBs as preferred first‐line antihypertensive treatment may significantly reduce the risk of dementia. If confirmed in randomized trials, these findings reflect a low‐cost and scalable opportunity to reduce dementia incidence world‐wide.
Fluid‐based biomarkers to facilitate clinical trial execution and interpretation
Authors: Zetterberg Henrik
Published: December 2020

Background

Most clinical trials in dementia prevention or disease modification have failed to meet their primary outcomes. During recent years, improved fluid‐ and imaging‐based biomarkers for Alzheimer’s disease (AD) pathologies have been developed. These can be used to increase the likelihood that the included patient population carries the pathology that the treatment is intended to ameliorate. However, the approach can be costly and results in frequent screen failures. Here, improved recruitment strategies that employ staged testing, from simple blood tests as pre‐screening tools to cerebrospinal fluid (CSF) analysis and neuroimaging for final diagnosis, are described and discussed.

Methods

The literature on blood‐, CSF‐, and imaging‐based biomarkers for amyloid and tau pathologies, as well as neurodegeneration, was reviewed. A number of staged testing scenarios were developed.

Results

The best‐established blood‐based biomarker for AD pathology is phosphorylated tau (P‐tau). Plasma P‐tau distinguishes AD patients from cognitively normal controls with areas under the curve (AUCs) above 90% and detects both tau and amyloid pathology, as determined by positron emission tomography (PET), with AUCs around 90%, already in pre‐dementia stages of the disease. This diagnostic performance exceeds that of plasma Aβ42/Aβ40 ratio. Plasma neurofilament light (NfL) concentration is increased in AD and correlates with neuroimaging evidence of neurodegeneration. Employing plasma P‐tau181 as a pre‐screening biomarker in the recruitment of patients to clinical trials of amyloid‐ or tau‐targeting therapies would reduce the number of screen failures by at least 50% and virtually remove the costs for negative PET examinations. Plasma NfL, being a general marker of neuronal injury, has the potential to detect side effects of drugs, e.g., clinically relevant encephalitis.

Conclusions

We propose that future clinical trials of drug candidates against AD‐related pathologies are designed so that a pre‐screening with plasma P‐tau takes place, increasing the likelihood that patients with AD pathology are included and subjected to costly but important examinations, such as amyloid and/or tau PET at baseline. In addition to yearly PET examinations, more frequent testing of blood biomarkers during the trial could also help identifying positive effects of the drug candidate (P‐tau and NfL), and side effects detrimental to neuronal health (NfL).
PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease
Authors: Ghisays Valentina , Lopera Francisco , Goradia Dhruman D. , Protas Hillary D. , Malek‐Ahmadi Michael H. , Chen Yinghua , Devadas Vivek , Luo Ji , Lee Wendy , Brown Christopher T. , Baena Ana , Bocanegra Yamile , Guzman‐Velez Edmarie , Pardilla‐Delgado Enmanuelle , Vila‐Castelar Clara , Fuller Joshua T. , Hu Nan , Clayton David , Smith Jillian , Thomas Ronald G. , Toga Arthur W. , Alvarez Sergio , Rios‐Romenets Silvia , Langbaum Jessica B. , Chen Kewei , Su Yi , Tariot Pierre N. , Quiroz Yakeel T. , Reiman Eric M. ,   API ADAD Colombia Trial Group
Published: December 2020

Background

In contrast to late onset Alzheimer’s disease (LOAD), the late clinical stages of autosomal dominant Alzheimer’s disease (ADAD) are associated with greater neuropathological evidence of cerebellar amyloid plaque (Aß) deposition. In this study, we used PET measurements of fibrillar Aß burden to characterize the presence and age at onset of cerebellar Aß deposition in cognitively unimpaired Presenilin‐1 (PSEN1) E280A mutation carriers from the world’s largest extended family with ADAD.

Method

Florbetapir and PiB PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and the Colombia‐Boston (COLBOS) longitudinal biomarker study were included. Template‐based cerebellar standard uptake value ratios (SUVR), using a known‐to‐be‐spared pontine reference region, were used to 1) compare 290 cognitively unimpaired 28‐56 year‐old mutation carriers and non‐carriers; 2) characterize associations among cerebellar‐to‐pontine SUVR and age, mean cortical SUVRs, and episodic memory performance; and 3) estimate the age at which cerebellar‐to‐pontine SUVRs begins to differ significantly in the carrier and non‐carrier groups.

Result

Compared to non‐carriers, cognitively unimpaired carriers had higher cerebellar‐to‐pontine florbetapir and PiB SUVRs (p<.0001). Mean cortical SUVRs were positively correlated with age and negatively correlated with episodic memory performance (p<.05). SUVRs began to distinguish carriers from non‐carriers at age 34, 10 years before the carriers’ estimated age at mild cognitive impairment onset.

Conclusion

This PET study provides evidence of cerebellar Aß plaque deposition in cognitively unimpaired mutation carriers starting years before their clinical onset. Additional studies are needed to clarify the impact of using a cerebellar versus pontine reference region on the power to detect and track ADAD progression, even in preclinical stages of this disorder.
β‐arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates
Authors: Woo JungA Alexa , Liu Tian , Fang Cenxiao , Castano Maria , Kee Teresa , Yrigoin Ksenia , Yan Yan , Cazzaro Sara , Matlack Jenet , Wang Xinming , Zhao Xingyu , Kang David E. , Liggett Stephen B.
Published: December 2020

Background

Frontotemporal lobar degeneration (FTLD) is second only to Alzheimer’s disease as a cause of dementia, and we find the scaffolding protein β‐arrestin2 is elevated in human brains with this condition, and is responsible for accumulation of pathological tau tangles. Increased β‐arrestin2 impairs tau clearance and promotes tau aggregation by impeding the autophagy cargo carrier p62/SQSTM1. Such activity requires β‐arrestin2 in its oligomeric form, an assembly state that is not involved with receptor binding. Virus delivered gene therapy to the brain with dominant‐negative mutant β‐arrestin2s ablates pathologic tau in neurons of a mouse model of FTLD‐tau, revealing a new strategy to mitigate tauopathy by targeting β‐arrestin2 oligomerization.

Method

mice: Arrb2−/−, tau P301S, and WT mice were all bred in the C57BL6 background. Patients samples: Frozen frontal cortex tissue samples were obtained from the Alzheimer’s Disease Research Center at Emory University. We used samples from FTLD‐tau diagnosed patients. Primary neuronal cultures, Proximity ligation assay (PLA), Immunocytochemistry and Immunohistochemistry, Sarkosyl extraction, Generation of rAAV9 and stereotaxic injections, Electrophysiology, and Atomic force Microscopy Imaging applications were used in this study.

Result

β‐arrestin2 levels in brains of FTLD‐tau patients and tau P301S transgenic mice were significantly increased. β‐arrestin2 increases tau stability without altering tau mRNA levels. Furthermore, genetic reduction of β‐arrestin2 mitigates tauopathy and synaptic dysfunction in tau P301S mice. β‐arrestin2 oligomerization is required for tau stability, and β‐arrestin2 oligomers increase tau levels by inhibiting self‐association of the autophagy cargo receptor p62/SQSTM1, impeding p62 autophagy flux. Hence, reduction of oligomerized β‐arrestin2 with virus encoding β‐arrestin2 mutants acting as dominant‐negatives markedly reduced tau‐laden neurofibrillary tangles in FTLD mice in vivo. Reducing β‐arrestin2 oligomeric status represents a new strategy to alleviate tau pathology in FTLD and related tauopathies.

Conclusion

Based on our findings, the effects of inhibiting β‐arrestin2 oligomerization would be expected to not only inhibit the development of new tau tangles, but also to clear existing tau accumulations due to this mechanism of enhancing tau clearance. Beyond tauopathy, it is conceivable that this strategy could also prove to be beneficial in other neurodegenerative diseases bearing proteinopathies that are cleared via p62.
Using a novel clinical prediction algorithm to enhance clinical trials in Alzheimer's disease
Authors: Stern Yaakov , Stallard Eric
Published: December 2020

Background

The course of Alzheimer’s disease (AD) is heterogenous, in part because of individual heterogeneity in the disease’s underlying biological changes. This heterogeneity can influence the efficacy and interpretation of clinical trials. We developed a Grade of Membershp (GoM) prediction model that can accurately predict time to important disease endpoints in individual patients. Here we present the model and discuss its implications for clinical trials in AD.

Method

The GoM model was developed in the Predictors 2 cohort. It incorporates 73 time‐varying categorical covariates spanning 11 measurement domains including cognition, function; psychiatric symptoms, motor signs/symptoms and APOE genotype. We then tested the model in the separate Predictors 1 data set, consisting of 252 patients with mild AD at first visit who were followed semi‐annually for up to 10 years. We applied the GoM model to data from each patient‘s first visit, which generates a baseline GoM status. We then generated predicted survival functions and used life table analyses to compare predicted and actual survival.

Result

The figure summarizes the actual survival curve for all patients, and the survival curves as predicted from the GoM model. The predictions fell well within the confidence intervals around the actual survival curve. We also divided the estimated survival into quintiles, and compared the predicted versus actual quintile‐specific survival curves. Again, the predictions generally fell well within the confidence intervals around the actual survival curves.

Conclusion

Our new GoM model, applied to an external population, generated accurate predictions of survival using only the data from the patient’s first visit. Any variable in the model can also be predicted, including specific cognitive and functional outcomes. The GoM model has great potential for the design and interpretation of clinical trials in three ways: 1) randomization can be optimized or evaluated by comparing the distribution of GoM status in control and treatment groups; 2) the model should predict disease progression well in the placebo group; individual deviations from model prediction in the treatment group could indicate specific treatment effects; 3) with sufficient validation, the model itself could be used in the place of a placebo group.
Asymmetry of plaque burden in amyloid mouse models
Authors: Biechele Gloria , Sacher Christian , Blume Tanja , Beyer Leonie , Sauerbeck Julia , Eckenweber Florian , Deussing Maximilian , Focke Carola , Parhizkar Samira , Lindner Simon , Gildehaus Franz Josef , von Ungern‐Sternberg Barbara , Baumann Karlheinz , Tahirovic Sabina , Kleinberger Gernot , Willem Michael , Haass Christian , Bartenstein Peter , Cumming Paul , Rominger Axel , Herms Jochen , Brendel Matthias
Published: December 2020

Background

Asymmetries of neuropathology, including amyloid‐β (Aβ) burden, are a well‐known phenomenon in patients with Alzheimer’s disease (AD). Yet the occurrence of asymmetric Aβ deposition in amyloid mouse models of AD is scantly documented. Therefore, we first aimed to investigate Aβ‐asymmetries in a comprehensive study of five different amyloid mouse models examined by Aβ‐ small animal positron‐emission‐tomography (PET). Second, we assessed whether any such asymmetries have an association with microglial activation.

Method

523 historical cross‐sectional [18F]‐florbetaben Aβ‐PET scans of five different amyloid mouse models (AppNL‐G‐F
, APP‐SL70, PS2APP, APP/PS1, and APPswe) and 27 wild‐type mice were analyzed. 136 of these mice (four models) had also undergone contemporaneous [18F]‐GE‐180 18kDa translocator protein (TSPO)‐PET for microglial activation. The asymmetry index (AI) between the left and the right forebrain was calculated for both tracers. AI values outside the 95%/99% confidence intervals of wild‐type mice were defined as having moderate/strong asymmetry. We also analyzed the AI of Aβ‐PET as a function of age and in correlation with TSPO‐PET AI and calculated extrapolated sample sizes required for analyses of single and combined hemispheres.

Result

Moderate/strong asymmetries of Aβ deposition were identified in 40%/30% of transgenic mice, occurring most frequently in the PS2APP and AppNL‐G‐F
models (see Figure 1). A significant left dominance in PS2APP and a significant right hemispheric dominance in APPswe mice were observed for Aβ deposition. There was no age dependency of AI, but there was a significant correlation between AIs of Aβ‐PET and TSPO‐PET (all R > 0.3, all p < 0.05; Figure 2). Asymmetry was associated with higher variance of SUVR in single hemispheres, leading to higher required sample sizes for a given power (see Figure 3).

Conclusion

Asymmetry of plaque neuropathology occurs frequently in amyloid mouse models of AD, contributing importantly to variance of results in single hemispheres. Concomitant asymmetry of microglial activation indicates a neuroinflammatory component to hemispheric predominance of fibrillary amyloidosis. Important lateralized distribution of fibrillar plaques has likely been a confounding factor in previous studies with Aβ mouse models and is not sufficiently considered.