bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning–based detection model of early Alzheimer's disease using wearable device and gait assessment
Authors: Jeon YoungHoon , Ho Thi Kieu Khanh , Kang Jaeyong , Kim Byeong C. , Lee Kun Ho , Song Jong‐In , Gwak Jeonghwan
Published: December 2021

Background

A method for diagnosing early stages of Alzheimer's disease (AD) is developed by analyzing human gait and training a machine learning classifier using signals obtained from inertial measurement unit. This patient‐friendly and cost‐effective method enables periodic monitoring, contributing to savings in treatment costs and effort.

Method

145 subjects (77 healthy controls, 68 Mild Cognitive Impairment) were employed to perform seven types of gait paradigms, including normal and complex walking. The gait of the employed subjects was measured by 7 shimmer devices, which consist of a three‐dimensional accelerometer and gyroscope. The acquired signal data is converted into 35 features including gait cycle. The extracted features are used to train an ensemble classifier based on machine learning with an oversampling method. In order to find the optimal combination in the ensemble model, an elimination technique was used to compare performance by removing single classifiers one by one. For performance comparison, the dataset is divided into training set/test set by leave‐one‐patient‐out cross‐validation, and several metrics such as accuracy and F1 score are used.

Result

The classifier for MCI detection classified severity to an accuracy of about 0.7 for 145 subjects. The combination of oversampling techniques and different single classifiers contributes to improved performance. In the seven walking experimental paradigms, the accuracy of the classification of normal walking without subtasks is about 0.67. O the other hand, the classification of walking with associative word‐speaking or counting numbers shows significant results with accuracy of 0.7413 and 0.7338, respectively.

Conclusion

Our proposed method predicts severity through efficient walking with less space‐time constraints. Subtasks that stress the brain in walking contribute to the performance improvement of the ensemble model with oversampling. These results demonstrate that our proposed method with gait features can be used as an early diagnosis model to quickly initiate early intervention and prevention strategies that slow the progress of dementia.
Characterization of AD pathology based on plasma biomarkers measured by a fully automated immunoassay system (HISCLTM series)
Authors: Watanabe Shunsuke , Ishiki Kengo , Yamashita Kazuto , Lukaszewska Teresa , Miura Masahiro , Irino Yasuhiro , Iwanaga Shigeki , Yoshida Tomokazu
Published: December 2021

Background

There have been a lot of studies on classification of Alzheimer’s disease (AD) based on its pathological process. These pathological changes have been defined by the ATN classification system (A : amyloid β (Aβ) deposition, T : pathogenic tau, N : neurodegeneration) based on cerebrospinal fluid (CSF) biomarker levels or neuroimaging. In order to promote research and practical application, it is necessary to develop a cost effective and minimally invasive technology. Therefore, we have developed plasma Aβ1‐40, Aβ1‐42, threonine‐181 phosphorylated tau (p‐tau181) and total‐tau immunoassay systems and reported that these plasma biomarkers levels were significantly different between AD and cognitively normal (CN). In this study we have measured biomarkers in other sample sets including mild cognitive impairment (MCI), and evaluated the performance in characterizing AD pathology, in the context of the ATN classification system.

Method

We measured commercially available plasma and CSF samples on the HISCLTM series, which can achieve high degrees of sensitivity and fast measurement times of 17 minutes, requiring only 10 to 30 µl of samples. The concentration of plasma and CSF biomarkers levels (Aβ1‐40, Aβ1‐42, p‐tau181, total‐tau) were measured and the significance of the difference between AD, MCI and CN groups was assessed.

Result

The AD group had lower Aβ1‐42/Aβ1‐40 ratio and higher levels of p‐tau181 and t‐tau compared to MCI or CN groups. The levels of plasma biomarkers in MCI group showed wide distribution compared to AD or CN group, suggesting these plasma biomarkers reflect the various pathological states of dementia in MCI patients. This might indicate that our plasma biomarker measurement systems represent characterization of AD pathological processes.

Conclusion

Our assay system revealed that the distribution of plasma biomarkers showed characteristic distribution in AD, MCI and CN groups, respectively. This result may indicate the possibility of practical diagnosis of AD pathology based on plasma biomarker ATN classification system. We aim to continue to measure other clinical sample sets for evaluation of the usefulness and universality of plasma biomarkers.
Stability in BMI over time is associated with a better cognitive trajectory in older adults
Authors: Beeri Michal Schnaider , Tirosh Amir , Lin HungMo , Golan Sapir , Boccara Ethel , Sano Mary , Zhu Carolyn W
Published: December 2021

Background

Despite the relevance of body mass index (BMI) to the risk of incident cognitive impairments and the subtle but consistent decrease in BMI which accompanies old age, there is limited evidence on the simultaneous changes in BMI and cognitive decline, which better reflect the natural course of both health phenomena. Whether BMI stability contributes to better cognitive trajectories is essentially unknown. To address this gap in knowledge we examined the longitudinal associations of changes in BMI over time with changes in cognition.

Method

We exploited longitudinal clinical data from 15,977 initially non‐demented older adults participating in the Alzheimer’s Disease Centers across the United States followed for an average of 5 years. In this longitudinal study, changes in BMI were defined as 1) last minus first BMI, 2) mean of all follow‐up BMIs minus first BMI, and 3) standard deviation (SD‐representing variability) of BMI change from baseline and all follow‐up visits. Linear mixed effect models assessed the association of each of the BMI change variables with cognitive decline, adjusting for a broad range of sociodemographic, cardiovascular, and functional measures.

Result

Participants averaged 73.5 (7.6) years of age and 15.6 (3.6) years of education; 59.2% were women and 80.9% Caucasians. Participants who had significant changes in BMI defined as an increase or decrease of >5% in BMI, or who had greater variability in BMI, had a faster rate of cognitive decline in global cognition and the specific cognitive domains. Furthermore, this pattern was consistent irrespective of whether a person had normal (BMI<25; N= 5747), overweight (BMI=25 to 29.99; N=6302), or obese (BMI>30; N=3928) BMI at baseline.

Conclusion

Our study provides new evidence that greater changes (or variability) in BMI over time are associated with a faster rate of cognitive decline suggesting that in initially non‐demented older adults, stability in BMI predicts a better cognitive trajectory. These results suggest a potential clinical value in tracking BMI change, which is simple to measure, as it may point to individuals whose cognition is declining.
Early identification of persons living with dementia at point‐of‐care hospitalization using the electronic medical record
Authors: Tan Zaldy S , Rhinehart Deana , Spivack Erica , Keklikian Maria , Cheng Susan
Published: December 2021

Background

Hospitalization for Alzheimer's disease and related dementias (ADRD) is the single largest expense in the U.S., accounting for two thirds of Medicare costs for ADRD estimated at $155 billion in 2020. Persons living with dementia (PLWD) are twice as likely to be hospitalized, have longer average lengths of stay, higher readmission and mortality rates and are at increased risk for institutionalization. A major challenge is the low rates of identification of PLWD upon admission to the hospital, preventing early institution of person‐centered collaborative care interventions that can improve patient outcomes.

Method

Two trained dementia nurse practitioners performed a prospective daily review of all patients age >70 years admitted to a large academic medical center for a period of 8‐weeks (1/26/2021 – 3/23/2021). The NPs performed a systematic keyword search of the EMR for ADRD diagnoses, which were confirmed through review of past medical history, outpatient primary care and consult notes, problem and medication lists. Hospitalized PLWD were analyzed for quality of care indicators.

Result

Of the 249 hospitalized patients (mean age 86.5 years;61% female) with ADRD diagnosis, 47 (18%) had dementia included in the admission diagnosis while 151 (61%) had dementia included in the admission history and/or assessment/plan. 71 patients (29%) had restraints ordered, 120 (48%) were prescribed psychoactive medications and 95 (38%) were put on restraints. Advance directives were completed for 122 (49%) of PLWD and 157 (63%) had a full code status. 149 (60%) had a previous inpatient admission and 57 (23%) had an ED visit in the last 12 months. Ninety‐five (38%) of hospitalized PLWD were discharged to institutional facilities.

Conclusion

There are low rates of inclusion of dementia in admission diagnoses and notes of hospitalized PLWD. In contrast, there are high rates of restraint use, psychoactive medication order and discharge to institutional facilities. Most PLWD admitted to the hospital has had a previous hospitalization in the past year. To our knowledge, this is the first study that utilized EMR‐based identification of ADRD diagnosis and tracking of hospital outcomes of PLWD. These findings represent opportunities for improvement in quality and outcomes of hospital care for PLWD.
Targeting microRNA‐485‐3p blocks Alzheimer's disease progression
Authors: Ryu JinHyeob , Koh HanSeok , Lee SangJoon , Lee HyoJin , Min JaeWoong , Iwatsubo Takeshi , Teunissen Charlotte E. , Cho HyunJeong
Published: December 2021

Background

Alzheimer’s disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction, which affects more than 44 million people worldwide. Currently, there is no effective therapy for AD despite its increasing global incidence; thus, effective treatment strategies for AD are urgently needed. While several drugs that decrease amyloid beta (Aβ) production or increase Aβ clearance in the brain have been identified, treatment with these drugs is poorly correlated with improvements in AD severity and cognitive dysfunction.

Method

Expression of miR‐485‐3p was analysed by real‐time PCR in the human frontal cortex (8 healthy controls (HC), 7 AD patients), precentral gyrus (6 HC, 8 AD), cerebrospinal fluid (CSF) (6 HC, 7 AD), plasma exosomes (10 HC, 17 mild cognitive impairment (MCI), 12 AD). Aβ 1–42 plaque immunofluorescence and tau pathology were imaged in primary cultured mouse neurons after lentivirus‐derived miR485‐3p transduction. MiR‐485‐3p antisense oligonucleotide (ASO, 1.5 μg) or control oligonucleotide formulated with the in vivo jetPEI reagent was injected into 8‐month‐old 5XFAD mice by ICV injection once weekly for two weeks. Behavioral tests were performed at 8 months and their brain pathology was examined after 8‐week‐washout at 10 months.

Result

We found that the miR‐485‐3p is overexpressed in brain tissues and CSF of AD patients, and its ASO reduces Aβ plaques, tau pathology, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR‐485‐3p ASO enhanced Aβ clearance via CD36‐mediated phagocytosis of Aβ in vitro and in vivo. We found that miR‐485‐3p ASO reduces apoptosis, which effectively decreases truncated tau levels. Further, miR‐485‐3p ASO reduced secretion of pro‐inflammatory cytokines, including IL‐1β and TNF‐α, and eventually relieved cognitive impairment.

Conclusion

Collectively, our findings suggest that miR‐485‐3p is a useful biomarker as well as a causative factor of the inflammatory pathophysiology of AD; furthermore, miR‐485‐3p ASO represents a candidate therapy for AD pathology and cognitive decline, establishing a new paradigm in the AD field.
Effect of multimodal non‐pharmacologic interventions on cognitive function for people with dementia: Systematic review
Authors: Sharew Nigussie Tadesse , LAM Simon Ching , Habtewold Tesfa Dejenie , Leung Angela Yee Man
Published: December 2021

Introduction

Dementia is a progressive brain degeneration characterized by a progressive deterioration in cognition and independent living capacity (Sobral, Pestana, & Paúl, 2015). Fifty million people are living with dementia globally. This number will be projected to grow to 82 million by 2030 and 152 million by 2050 (Alzheimer's Disease International, 2020. Since dementia is complex syndrome, multimodal non‐pharmacologic interventions (MNPIs) are highly recommended (Dannhauser et al., 2014; Graessel et al., 2011; Han et al., 2017; Yang et al., 2019). Currently, there is little available evidence to determine which multimodal interventions are effective for cognitive function improvement.

Method

A comprehensive search was done in PubMed, EMBASE, CINHAL, Web of Science and Medline international databases. The inclusion criteria of this review were; concerned adults with primary diagnosis of dementia, measured cognitive function outcome, used two or more type of interventions, published in English language and employed controlled trial study design. The quality appraisal of the studies was done by Cochrane risk of bias assessment tools for randomized controlled trail and non‐randomized controlled trial studies (Sterne et al., 2016; Sterne et al., 2016).

Results

Fourteen RCTs and five non‐RCT studies were included in the systematic review. Nearly ninety percent of studies resulted in an improvement or maintenance of cognitive function among people with dementia. Integrated, multicomponent and dyadic based interventions implemented for longer duration resulted in improve cognitive function of people with dementia. The combination of three modes of non‐pharmacologic intervention that includes exercise, music, and cognitive training with intervention design of more than three sessions per week for at least 12 ‐ 48 weeks is recommended.

Conclusion

This study showed that multimodal non‐pharmacologic interventions might improve cognitive functions among people with dementia. Future high quality randomized controlled trail studies with repeated‐measured design on the combined effect of physical exercise, music and cognitive training on cognitive function for people with dementia is recommended.
Improved functional connectivity after a 6‐month ketogenic supplementation in mild cognitive impairment
Authors: Roy Maggie , Edde Manon , Fortier Melanie , Croteau Etienne , Castellano Christian‐Alexandre , St. Pierre Valerie , Vandenberghe Camille , Morin Marie‐Christine , Langlois Francis , Bocti Christian , Fulop Tamas , Descoteaux Maxime , Cunnane Stephen
Published: December 2021

Background

Ketones, the brain’s alternative fuel to glucose, bypass the brain glucose deficit in mild cognitive impairment (MCI). The BENEFIC trial conducted in MCI showed improved measures of cognition in multiple domains after a 6‐month ketogenic intervention [Fortier et al. 2019]. Functional connectivity in the dorsal‐attention network (DAN) deteriorates early in MCI, and prior to changes in the ventral‐attention network [Zhang et al. 2015]. We aimed to assess whether improved cognitive outcomes in the BENEFIC Trial were linked to improved brain functional connectivity.

Method

Participants in this 6‐month intervention were randomized to a placebo (n= 15) or ketogenic medium chain triglyceride (kMCT; n= 17) drink. A neurocognitive battery and brain imaging were performed pre‐ and post‐intervention. Functional connectivity was computed from resting‐state functional magnetic resonance images. Independent component analysis (FSL Melodic) was used to segment seven major resting‐state networks (DAN, ventral‐attention, frontoparietal, limbic, somatomotor, default‐mode and visual) [Yeo et al. 2011]. Regional cortical ketone (11C‐acetoacetate) and glucose (18F‐fluorodeoxyglucose) metabolic rates were also quantified using positron emission tomography (PET).

Result

Changes (post ‐ pre) in DAN functional connectivity was significantly higher in the kMCT group vs placebo (P= 0.024). After correction for age, sex, education, ApoE status and intracranial volume, the significant difference between groups was still present, with a large effect size (partial h2= 0.16; P= 0.043; Figure 1). Connectivity in no other networks was significantly different between groups. Changes in attention and processing speed composite Z‐score (r= 0.42; P= 0.021) and specific tests targeting attention (Trail Making visual scanning and number sequencing conditions) were significantly associated with the increased DAN functional connectivity. Change in ketone uptake specifically in DAN cortical regions (Figure 2C) was significantly higher in the kMCT vs placebo group (P= 0.001) and was directly associated with the improved DAN functional connectivity, with a large effect size (r= 0.69; P= 0.002; Figure 3).

Conclusion

We show that a 6‐month ketogenic intervention improves DAN functional connectivity in MCI, an improvement that is directly linked to increased energy (ketone) supply to the DAN. The beneficial effect of ketones on cognition in MCI may be linked to improved DAN connectivity.
E2F4DN‐based gene therapy recovers long‐term potentiation and hippocampal‐dependent memory in homozygous 5xFAD mice
Authors: Sánchez‐Puelles Cristina , Perea Gertrudis , Frade Jose María
Published: December 2021

Background

Neuronal cell‐cycle reentry, followed by DNA duplication (tetraploidization), precedes and recapitulates Alzheimer´s disease (AD) neuropathological hallmarks (Arendt et al., 2010; López‐Sánchez et al., 2017). E2F4 is expressed by neurons and becomes phosphorylated in APP/PS1 mice and in Alzheimer patients. We have demonstrated that the phosphorylation of two conserved Thr residues of E2F4 is necessary to induce neuronal tetraploidization and cognitive loss in AD (Lopez‐Sanchez and Frade, 2017; López‐Sánchez et al., 2017). Thus, it was developed a therapy consisting in neuronal expression of a dominant negative form of E2F4 (E2F4DN), not phosphorylatable. This therapy has been patented (US9567384B2, EP2783696B1, JP6100276B2), and is licensed by Tetraneuron. Initial stages of AD are proposed to be linked to alterations in synapse function, responsible for the cognitive deficits observed in AD (Knafo et al., 2016). Thus, we hypothesized that viral expression of E2F4DN could correct the synaptic dysfunction associated to AD.

Method

Hippocampal primary cultures were prepared and neurons were transduced with a viral vector containing E2F4DN. Through whole‐cell recordings spontaneous synaptic activity (sEPSC) was analyzed (control n=15, E2F4DN n=21). Afterwards E2F4DN was expressed in vivo (AAV‐E2F4DN intravenous administration) in six‐week old homozygous 5xFAD and WT mice and behavior and electrophysiology was achieved (6‐months‐old). Cognition was analyzed in not injected (n=7) and injected WT (n=5) and not injected (n=19) and injected 5xFAD (n=5) mice through novel‐object location and contextual fear conditioning test. Synaptic function was evaluated by electrophysiological recordings of field excitatory postsynaptic potential (fEPSPs) in CA3‐CA1 synapses in acute slices from WT (not injected n=10, injected n=7) and 5xFAD mice (not injected n=11, injected n=8), both basal transmission and LTP (3xTBS) was examined.

Result

We demonstrated that E2F4DN does not alter basal properties of hippocampal neurons in culture. Intravenous administration of AAV‐E2F4DN improves basal synaptic transmission and reverts LTP inhibition, observed in not injected 5xFAD mice. Furthermore, this LTP recovery leads to cognitive improvement. 5xFAD mice treated with our therapy present a notably improvement in two hippocampal‐dependent memory tasks compared to not injected 5xFAD mice.

Conclusion

E2F4DN‐based gene therapy represents a promising approach for AD treatment with capacity to prevent cognitive decline associated to the disease.
The use of the Cognitive Change Questionnaire by community health workers as dementia screening method
Authors: Feitosa Raul Raposo Pereira , Frota Norberto Anizio Ferreira , Maia Fernanda Martins , Feitosa Esther De Alencar Araripe Falcao
Published: December 2021

Background

The Cognitive Change Questionnaire (CCQ) was a tool developed in Brazil to evaluate cognitive changes (1). This work evaluates the applicability of the CCQ by Community Health Workers (CHW), as a way of screening for dementias.

Method

This study is being carried out in a small city in the state of Ceara, Brazil. Community health workers received training on what is dementia and how to apply the CCQ. The CHW is applying the CCQ to all individuals in the municipality, aged 60 or over, approximately 2,273 individuals, and 500 individuals have been evaluated so far. After the application of the test, all individuals considered altered will be evaluated by physicians specialized in cognitive neurology. Part of the negatively screened patients will also be chosen, at random, for evaluation by specialist doctors.

Result

The main result to be measured will be the sensitivity values of the test as a way to screen elderly patients with dementia. As a secondary data, the prevalence of dementia will also be obtained.

Conclusion

It is expected that the application of the QCC by CWH will be an excellent screening tool for dementias and, therefore, improve the identification and care of these patients. 1. Damin AE, Nitrini R, Brucki SMD. Cognitive Change Questionnaire as a method for cognitive impairment screening. Dement Neuropsychol. 2015;9(3):237–44.
Relationship between platelet derived growth factor receptor‐β and Alzheimer’s biomarkers in a racially diverse, high‐risk cohort
Authors: Butts Brittany , Miners Scott , Kehoe Patrick G. , Hu William T. , Huang Hanfeng , Verble Danielle D. , Zetterberg Henrik , Zhao Liping , Wharton Whitney
Published: December 2021

Background

With the increasing prevalence of Alzheimer’s disease (AD), there is an increased need for systematic research targeting preclinical pathophysiologic mechanisms of AD development for high‐risk, racially diverse, populations. Neurovascular dysfunction and blood brain barrier (BBB) breakdown likely occur early in AD pathology, however their relationship to AD biomarkers in preclinical populations are not well known. Soluble platelet derived growth factor receptor‐β (sPDGFRβ), a novel CSF biomarker of BBB‐associated capillary pericyte damage, is shed from injured human pericytes and is associated with AD pathology. Here we tested the hypothesis that sPDGFRβ is related to CSF AD biomarkers and CSF markers of vascular dysfunction in a cohort of Black/African American (B/AA) and non‐Hispanic White (NHW) participants.

Method

Cognitively unimpaired, middle‐aged (45‐65 years) adults with a parental history of AD were enrolled. CSF was collected at baseline and 2 years for measurement of sPDGFRβ, AD biomarkers (Aβ and tau), and markers of vascular dysfunction (ACE activity, and VCAM‐1).

Result

Participants (N=70) were mostly female (69%), well educated (81% college or greater), and 34% identified as B/AA. Forty‐eight percent were ApoEε4 positive. At both baseline and 2 years sPDGFRβ was positively correlated with P‐tau (r=.380, p=.003; r=.356, p=.008), T‐tau (r=.466, p<.001; r=.485, p<.001), Aβ40 (r=.439, p=.001; r=.454, p=.001), ACE‐1 activity (r=.363, p=.003; r=.272, p=.041), and VCAM‐1 (r=.511, p<.011; r‐=.401, p=.002) and negatively correlated with Aβ42/40 (r=‐.282, p=.024; r=‐.399, p=.002), controlling for age, sex, race, and education. At both time points, AAs had lower sPDGFRβ, P‐tau, T‐tau, and Aβ40 and higher Aβ42/40 compared to NHWs.

Conclusion

sPDGFRβ was associated with tau hyperphosphorylation (P‐tau) and neurodegeneration (T‐tau) in a cohort of cognitively unimpaired middle‐aged adults at risk for AD. Pericyte loss may relate to disease pathology early in AD development in at‐risk individuals, providing a potential mechanistic target for early intervention and prevention strategies. sPDGFRβ was associated with ACE‐1 and VCAM‐1, suggesting a potential role for endothelial activation in early BBB breakdown. As we found differences in AD biomarkers by between AA and NHW participants, reference ranges for these biomarkers may vary by race. More research is needed examining pre‐clinical disease pathways in diverse populations.
Developing interdisciplinary participatory practices to disrupt the status quo in dementia research
Authors: Sood Garima , Gawryluk Jodie , Couture Daisy , Raber Caylee , Puurveen Gloria
Published: December 2021

Background

In dementia research, there is a growing emphasis on generating meaningful research collaborations with people with lived experiences (PWLE). This brings attention to different participatory methods that have the ability to shift perspectives in research and deepen engagement with both PWLE and researchers. However, how participatory methods are realized in practice across the research process requires further investigation; as such, the purpose of this study was to:

1) Explore existing interdisciplinary practices, tools and strategies that promote partnership with PWLE to amplify lived experiences and foster inclusivity; and

2) Identify gaps and opportunity spaces to further develop person‐centred and collaborative research tools and practices.

Method

The Alzheimer Society of B.C., Emily Carr University’s Health Design Lab and researchers from the University of Victoria and the University of British Columbia partnered at the 2021 Dementia Lab conference to conduct two virtual participatory workshops. The workshops gathered 38 participants including researchers, interdisciplinary creatives, designers and PWLE. Participants were invited to share their experiences in dementia research and their vision of how to foster best‐practices. Design methods such as envisioning, imagining, visualizing and drawing were adopted to facilitate dialogue and bring out tacit knowledge held by participants.

Results

Inductive analysis of workshop data revealed that interdisciplinary practices are adopted in different dementia‐related projects to foster collaboration with PWLE, which contributes to levelling out epistemological hierarchies. The following four overlapping themes emerged from the analysis: 1) Relationships of reciprocity: Translating research findings into community support and ensuring participants are invited to participate in knowledge making and sharing. 2) Pace: Developing research strategies, objectives and methods that allow for a slower pace to afford generative and person‐centred outcomes. 3) Power dynamics: Shifting hierarchical power relations in research activities. 4) Generative and continuous practices: Embedding continuity of knowledge and ongoing relationships into research projects to ensure that acquired knowledge can be continually nourished, adopted and updated.

Conclusion

By centring perspectives of people with lived experiences of dementia and fostering interdisciplinary collaborations, generative and person‐centred research practices can propel a shift in the status quo of dementia research, while empowering people living with dementia.
Combination of baicalein and trans‐chalcone synergistically reduces amyloid beta and its toxicity in yeast
Authors: Dhakal Sudip , Macreadie Ian George , Adhikari Benu , Ramsland Paul
Published: December 2021

Background

There has been a long quest to uncover effective therapeutic strategy to prevent or cure AD as current strategies only support as palliative care. This study utilizes unmodified and genetically modified Saccharomyces cerevisiae as model organisms to screen and find potential natural bioactive compounds that can reduce the levels of amyloid beta and associated toxicity.

Methods

Eleven selected naturally occurring bioactive compounds namely mangiferin, quercetin, rutin, resveratrol, epigallocatechin gallate (EGCG), urolithin A, oleuropein, rosmarinic acid, salvianolic acid B, baicalein and trans‐chalcone at specific concentration (50µM) were screened for their ability to change intracellular green fluorescent protein (GFP) tagged Aβ42 levels, in vivo anti‐amyloid properties using thioflavin‐S fluorescent dye and induce heat stress response using the yeast heat stress reporter that expresses mCherry red fluorescent protein under control of a heat shock promoter containing heat shock elements (HSEs). Furthermore, the two compounds with highest activity in all three screens were combined together in varying concentrations of each to study the underlying combination ability to reduce GFP‐Aβ42, their effect on growth, turnover of native Aβ42 and reactive oxygen species.

Results

The bioactive compounds reduced intracellular GFP‐Aβ42 levels (except mangiferin) and intracellular amyloid fibrils (except resveratrol and EGCG) in yeast models significantly with highest effect shown by baicalein and trans‐chalcone. Among the bioactive compounds, quercetin, rutin, rosmarinic acid, baicalein and trans‐chalcone significantly induced heat stress reporter with highest effect demonstrated by baicalein and trans‐chalcone. Furthermore, the combinations of baicalein and trans‐chalcone showed synergistic ability to reduce GFP‐Aβ42. Although some of the combinations were found growth inhibitory, a combination of 50μM trans‐chalcone and 30μM baicalein was found to be cytoprotective as well as an effective reducer of GFP‐Aβ42. In addition, the combination of the two compounds showed synergy in reducing ROS in yeast cells expressing native Aβ42 and reduced the Aβ42 protein levels by nearly 80%.

Conclusion

The findings of the study suggest that the combination of baicalein and trans‐chalcone can be a therapeutic strategy to cure or at least prevent AD. However, further studies are recommended to ascertain that similar cytoprotective activity is observed in humans and optimization of dosage to observe best effect.
Proteomic analysis of Parkinson’s disease patient cohorts show similarities in mechanism to Alzheimer’s disease
Authors: Winchester Laura M. , Lawton Michael , Barber Imelda S. , Evetts Samuel , Ryan Brent , Wade‐Martins Richard , Ben‐Shlomo Yoav , Hu Michele , Grosset Donald G. , Nevado‐Holgado Alejo J. , Lovestone Simon
Published: December 2021

Background

Alzheimer’s Disease and Parkinson’s Disease (PD) share similarities in phenotype and an overlap between disease subtypes and diagnostic testing which implies a link between some of the neurodegenerative processes.

Here, we report the initial results for proteomic assays on two longitudinal PD cohorts demonstrating dementia‐like protein dysregulation signatures as well as PD specific signatures in the largest proteomics collection of PD patients to date.

Method

We used aptamer‐based technology (SOMAmer assay, SomaLogic®) to measure 4003 proteins in 1599 serum samples collected from two observational longitudinal cohorts: Oxford Parkinson’s Disease Centre Discovery cohort (OPDC) and the UK Tracking Parkinson’s cohort. Clinical measures of disease progression included the Movement Disorders Society Unified Parkinson’s Disease Rating Scale part III (UPDRS) and Montreal Cognitive Assessment (MoCA) adjusted for education years. The sample set included 319 controls.

We performed dysregulation analysis on log2 transformed data using linear models corrected for age, gender, and cohort. Enrichment analysis was implemented in the R library clusterProfiler using the KEGG and GO databases. Comprehensive co‐expression analysis was performed using WGCNA.

Result

Initial pathway analysis showed that the main significantly dysregulated protein pathways of case status were the Complement and coagulation cascades (p = 0.0086) and Protein digestion and absorption (p =0.0152). The Fat digestion and protein absorption pathway was enriched for dysregulated proteins associated to the UPDRS measure (p = 0.00142). Using co‐expression analysis we identified a module of 625 proteins with a significant relationship to disease status (p = 3.20x10‐07) and the movement (p = 2.35 x10‐05) and cognition (p = 0.005) endophenotypes. This module was enriched for proteins involved in axon guidance in addition to the complement and coagulation cascades and protein digestion and absorption found in initial analyses.

Conclusion

Using a comprehensive profiling analysis of protein expression in two unique longitudinal PD cohorts we demonstrate the overlap between neurodegenerative disease types as well as highlight unique PD associations with potential mechanistic links to gut processes. This will have implications for further analysis of these PD cohorts for further mechanistic analysis and more importantly biomarker detection.
Single and multiple ascending dose studies in healthy volunteers to assess the safety and PK of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme
Authors: Lowe Stephen L , Goldsmith Paul , Phipps Krista M , Kevin Donnelly B , Biglan Kevin , Mancini Michele , Nuthall Hugh Norman , Mergott Dustin J. , Kielbasa William
Published: December 2021

Background

LY3372689, an OGA enzyme inhibitor, is being developed as a potential treatment for tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. We report the safety and pharmacokinetics (PK) of LY3372689 after single and multiple oral doses in healthy volunteers (HV).

Method

The single ascending dose (SAD) and multiple ascending dose (MAD) studies were single center, subject‐ and investigator‐blind, placebo‐controlled and randomized. In the SAD study [NCT03819270], 6 LY3372689 dose levels up to 16 mg and placebo were evaluated. In the MAD study [NCT04106206], LY3372689 (1, 3 and 7 mg) or placebo was given once daily (QD) for 14 days. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical exams, and neurological exams. Plasma pharmacokinetics (PK) was assessed in the SAD and MAD studies.

Result

In the SAD, 23 HV (15 males, 8 females; 22 – 63 years) participated, of which 18 HV completed. In the MAD, 40 HV (5 males, 35 females; 29 – 65 years) participated in the study, of which 39 HV completed. LY3372689 was generally well tolerated up to the highest dose in each study, and no serious AE were reported. In the SAD, 40 treatment‐emergent AEs (TEAEs) were reported, which were mostly mild in severity. The most common TEAEs were headache, nausea, pain in extremity, pain of skin, vessel puncture site pain, and limb discomfort. In the MAD, 42 TEAEs were reported, all of which were mild in severity. The most reported TEAE was headache. In both studies, there were no clinically significant changes in safety laboratories, including markers of inflammation, muscle injury, hormones and hepatoxicity. Following QD dosing of LY3372689, the tmax and t1/2 was about 1 hour and 6 hours, respectively, and LY3372689 exposure accumulation was minimal. Renal clearance was not a major contributor of LY3372689 elimination.

Conclusion

LY3372689 demonstrated an acceptable safety and PK profile following single and multiple doses of LY3372689 in HV. These results support investigation of LY3372689 in efficacy trials for tauopathies and help support dose selection for those trials.
TaPiscine: An effort‐based decision‐making task for apathy assessment in people with neurocognitive disorders
Authors: Zeghari Radia , Lockwood Patricia L , L'Yvonnet Thibaud , Jo Cutler , Robert Philippe , Manera Valeria
Published: December 2021

Background

Apathy is a common neuropsychiatric symptom in Neurocognitive Disorders (NCD). It is characterized by a significant reduction of goal‐directed behaviors in the domains of cognition, behavior, emotions, and social interactions. Goal‐directed behaviors can be investigated using effort‐based decision paradigms, allowing computational models to quantify sensitivity to effort and reward (and their combination) in a systematic way [1]. Our study used an effort‐based decision paradigm to investigate apathetic symptoms in a clinical context with older people with NCD and subjective cognitive decline (SCD).

Method

We recruited 33 participants with mild NCD or SCD from the Memory Center in Nice (24 females, mean age= 74 years, mean MMSE score = 27.1). We assessed self‐reported apathy using the Apathy Motivation Index (AMI) and the Dimensional Apathy Scale (DAS). We also assessed self‐reported fatigue (Multidimensional Fatigue Inventory, MFI), anhedonia (Snaith‐Hamilton Pleasure Scale, SHAPS), and depression (Geriatric Depression Scale, GDS). The effort‐based decision task consisted of choosing to perform an action (taping as quickly as possible on a tactile tablet to fill a virtual pool corresponding to 25%, 50%, 75% and 100% of the maximum individual effort) to obtain a specific reward (3, 6 or 9 credits to discover pictures), or to rest to ensure 1 credit. For each subject, we extracted a parameter (K) representing the degree to which a reward is devalued by effort.

Results

We divided participants into two groups with high and low AMI scores using a mean split. Results suggested that the K‐parameter was almost significantly lower in subjects with higher apathy (U=86, p=0,072). Further and more detailed analyses will be performed once reached a sample size of 50 subjects (end of June 2021).

Conclusions

Effort‐based decision tasks may be employed also in people with NCD, and may help to differentiate patients with low and high apathy. The study is ongoing, and a bigger sample will allow to better characterize these results. Reference: [1] Lockwood, P., Hamonet, M., Zhang, S. et al. Prosocial apathy for helping others when effort is required. Nat Hum Behav. 1, 0131 (2017). https://doi.org/10.1038/s41562‐017‐0131
Metabolomic signatures of dual decline in memory and gait: An aging phenotype of high risk of dementia
Authors: Tian Qu , Shardell Michelle D. , Tanaka Toshiko , Kuo Pei‐Lun , Resnick Susan M. , Ferrucci Luigi
Published: December 2021

Background

Our recent meta‐analysis of 6 geographically and culturally diverse aging studies has shown that older adults with dual gait and memory decline had a synergistically greater hazard of dementia than those with memory decline or gait decline only. Mechanisms underlying this increased risk are unknown. We hypothesize that those with dual decline have specific pathophysiological pathways to dementia.

Method

In the Baltimore Longitudinal Study of Aging, we compared rates of change in 455 plasma metabolites from 26 biochemical classes among dementia‐free participants aged 50 and older who experienced dual decline (n=114), gait decline only (n=167), memory decline only (n=168), and no decline (n=406) using linear mixed‐effects models. Longitudinal data on gait, memory, and Biocrates p500 metabolomics were collected simultaneously over an average of 6.6 years. Analyses were adjusted for batch, demographics, baseline memory and gait, education, and APOE e4 carrier status. We further performed enrichment analysis.

Result

After covariate adjustment, rates of change in 18 metabolites significantly differed among four groups (q<0.05). Top 10 ranked metabolites were from classes nucleobases (hypoxanthine), lysophosphatidylcholines (LPC C18:0, C16:0, C17:0, C18:1, C18:2), and ceramides (d16:1/24:0, d18:2/24:0, d16:1/23:0, d18:1/24:0) (Figure 1). LPCs, ceramides, and amino acids were significantly enriched (p<0.05). Compared to no decline group, memory decline only group had greater changes in 21 metabolites enriched for PCs, LPCs, and amino acids. Gait decline only group had greater changes in 106 metabolites enriched for triglycerides, ceramides, and cholesteryl esters. Dual decline group had greater changes in 121 metabolites enriched for LPCs, amino acids, and triglycerides (p<0.05). After multiple comparisons adjustment, LPC C18:0 showed greater decrease in dual decline group, and PC C32:2 showed greater increase in gait decline only group (q<0.05).

Conclusion

Metabolite changes over time may underlie age‐related decline in memory, gait speed, or both, especially in LPCs, ceramides, and amino acids. Older adults experiencing dual decline have the most extensive alterations in metabolic profiling, especially in LPCs, triglycerides, and amino acids. Notably, these metabolites are main building blocks for cardiolipin, an essential lipid for regulation and assemblage of electron transport complexes and mitochondrial morpho‐functional architecture. Pathway analyses and further validation are warranted.
Amyloid status is associated with deficits in connected speech language
Authors: Van Hulle Carol A. , Jonaitis Erin M. , Betthauser Tobey J. , Kollmorgen Gwendlyn , Suridjan Ivonne , Andreasson Ulf , Carlsson Cynthia M. , Asthana Sanjay , Johnson Sterling C. , Zetterberg Henrik , Blennow Kaj , Mueller Kimberly D.
Published: December 2021

Background

Subtle changes in connected speech language (CSL) comprising fluency disruptions and limited semantic content are present in preclinical stages of Alzheimer’s disease (AD) and dementia. Our prior research suggests that individuals identified by PET imaging as amyloid‐positive experience more rapid decline of semantic content than those without amyloid. Here we expand our analyses to additional CSL measures sensitive to nascent deficits in communication.

Method

Study participants were enrolled in Wisconsin Alzheimer’s Disease Research Center (n= 103) or the Wisconsin Registry for Alzheimer’s Prevention (n= 223), had available cerebrospinal fluid (CSF) measurements, and 1‐4 CSL samples. CSF biomarkers were measured using the exploratory Roche NeuroToolKit assays, a panel of automated robust prototype immunoassays (Roche Diagnostics International Ltd). Speech samples (N=740) were recorded while describing the “Cookie Theft” picture from the Boston Diagnostic Aphasia Examination. The majority of participants (65%) provided ≥ 2 language samples across biennial visits. Moving average types‐tokens ratio (MATTR), content information unit (CIU) density, CIUs per minute, words per minute, and filled pauses were extracted from speech samples. Linear mixed effects models were used to test moderation of age related changes CSL samples by amyloid status (Aβ42/Aβ40 ≥ .046), where age at study visit is the measure of time. ovariates gender, years of education, and number of CSL visits (i.e., practice effects) were included as fixed effects.

Result

Baseline demographics and study variables stratified by amyloid status are shown in Table 1. CSF amyloid status did not moderate longitudinal changes in any of the CSL outcomes (Figure 1). After dropping these non‐significant interactions, amyloid‐positive individuals expressed fewer CIUs total and per minute and slightly more filled pauses (Table 2). We also found a significant decline with age in CSL outcomes MATTR, CIUs per minute, and words per minutes. The pattern of results was unchanged after excluding nineteen individuals with cognitive impairment from analyses.

Conclusion

We found that amyloid burden associated with connected speech measures reflecting semantic content and word retrieval. CSL is a ‘digital biomarker’ that shows promise as a measure of language; future work will continue to explore longitudinal relationships between CSL and AD biomarkers.
Associations between gut microbiota composition and AD biomarkers
Authors: Verhaar Barbara J.H. , Hendriksen Heleen M.A. , Leeuw Francisca A. , Doorduijn Astrid S. , Leeuwenstijn Mardou , Teunissen Charlotte E. , Berckel Bart N.M. , Barkhof Frederik , Scheltens Philip , Kraaij Robert , Duijn Cornelia M. , Nieuwdorp Max , Muller Majon , Flier Wiesje M.
Published: December 2021

Background

Several studies have reported alterations in gut microbiota composition of Alzheimer’s disease (AD) patients. However, the observed differences are not consistent across studies. We aimed to investigate associations between gut microbiota composition and clinical biomarkers of AD using machine learning models in patients with AD dementia, mild cognitive impairment (MCI) and controls.

Method

We included 169 patients from the NUDAD project, comprising 33 with AD dementia (66±8 years, 46%F, MMSE 21[19‐24]), 21 with MCI (64±8 years, 43%F, MMSE 27[25‐29]) and 115 controls (62±8 years, 44%F, MMSE 29[28‐30]). Fecal samples were collected and gut microbiome composition was determined using 16S rRNA sequencing. Clinical parameters of AD included clinical diagnosis, cerebral spinal fluid (CSF) amyloid and phosphorylated tau (pTau) status, positron emission tomography (PET) amyloid status, and MRI visual scores. Associations between gut microbiota composition and dichotomized clinical parameters of AD were assessed with separate machine learning classification models using XGBoost with nested cross‐validation. The model with the highest area under the curve (AUC) was selected for logistic regression, to assess associations between the 20 best predicting microbes (cumulative sum scaled counts) and the outcome measure from this machine learning model while adjusting for age, sex, and BMI.

Result

The machine learning prediction for amyloid status (CSF) from microbiota composition had the highest AUC. Top predicting microbes included several short chain fatty acid (SCFA)‐producing species. In the logistic regression models, these microbes were significantly associated with lower odds of amyloid positive status, and included Eubacterium ventriosum group spp. (OR 0.49 (0.30‐0.76) per SD increase in counts, p = 0.002), Marvinbryantia spp. (OR 0.55 (0.34‐0.85), p = 0.009), Coprococcus catus (OR 0.58 (0.36‐0.89), p = 0.017), Roseburia hominis (OR 0.59 (0.38‐0.90), p = 0.018), Odoribacter splanchnicus (OR 0.51 (0.30‐0.82), p = 0.008), Lachnospiraceae spp. (OR 0.58 (0.36‐0.89), p = 0.014), and Ruminococcaceae spp. (OR 0.44 (0.25‐0.71), p = 0.002).

Conclusion

Gut microbiota composition had the strongest association with amyloid status among the clinical biomarkers examined. We extend on recent studies that observed associations between SCFA levels and AD biomarkers by showing that higher abundances of SCFA‐producing microbes were associated with lower odds of amyloid positive status.