bluuebunny/crossref_metadata_2025 huggingface dataset:
The salivary Tau protein as a biomarker for Alzheimer's disease
Authors: Santos Gustavo A.A. , Fazan Valeria Paula Sassoli , Pardi Paulo Celso
Published: December 2021

Background

Biomarkers can be detected in blood levels and more recently the viability of their identification in salivary samples has been verified. We believe that salivary biomarkers can be used to support behavioral assessments and thus serve as a diagnostic model for the identification of AD at an early stage

Method

This is a case‐control study carried out in patients diagnosed with probable AD and cognitively healthy patients without AD. A total of 60 patients were selected: 30 do not have Alzheimer's disease; 30 are patients with Alzheimer's disease. After processing the saliva collected in the laboratory, we used the ELISA method with adaptation of the kits for CSF and other components for saliva. The patients came from long‐term care facilities for the elderly and had medical follow‐up.

Result

We observed that the salivary tTAU concentration in patients with Alzheimer's is significantly lower, with a reduction of 35.5% compared to patients without AD, confirming the hypothesis that tTAU can be used as a biomarker for AD.

Conclusion

There is an inverse correlation between salivary TAU and CSF concentrations. Previous studies reinforce our view that there is an increase in pTAU and a reduction in tTAU in Alzheimer's patients. New studies need to be carried out with a greater diversity of groups and the inclusion of other biomarkers that can correlate the pathophysiological process of the disease with the respective concentrations.
PRIME uncovers circadian oscillation patterns and links with Alzheimer’s disease in untimed genome‐wide gene expression data across multiple regions of human brain
Authors: Wu Xinxing , Peng Chong , Wilcock Donna M. , Jicha Gregory A. , Cheng Qiang
Published: December 2021

Background

The disruption of brain circadian rhythm is a major symptom of AD patients. Recent studies and accumulating clinic evidence have suggested that this symptom usually occurs in the early phase of AD and probably precedes cognitive impairment development; however, the full circadian rhythm orchestration of gene expression in the human brain and its inherent associations with AD currently remain unknown. The main barrier to studying circadian rhythmic patterns of the whole‐genome gene expression is the requirement of time labels of brain tissues, which is hard to obtain or inaccurate. Indeed, current existing circadian rhythm analyses rely on the timestamps of samples.

Method

This study aims to explore the relationships between circadian rhythms of brain regions and AD with untimed genome‐wide gene expression data. To this end, we developed and presented an innovative, comprehensive, unsupervised machine‐learning based approach based on principal component analysis (PCA) and matrix factorization (MF), called PRIME, to detect and analyze oscillation patterns in untimed high‐dimensional data across multiple brain regions. PRIME captures oscillatory patterns in the latent space underlying the gene expression data without requiring time stamps of brain tissue samples.

Result

To demonstrate PRIME’s utility, firstly, we validated it by a time course expression dataset from mouse liver (Figs. 1‐2) as a cross‐species and cross‐organ validation, because this dataset has systematically recorded time labels. Then, we applied it to studying oscillation patterns in genome‐wide gene expression from 19 human brain regions of controls and AD patients. Our experiments showed that there exist clear synchronized oscillation patterns in 15 union brain regions of normal controls (Fig. 3). In sharp contrast, the synchronized oscillation patterns became either disappear or weakened for AD‐affected brains (Fig. 4). Additionally, we provided necessary rules to infer AD’s impacts on human brain regions (Table 1).

Conclusion

We developed a novel comprehensive approach, called PRIME, to detect and analyze rhythmic oscillation patterns in untimed high‐dimensional gene expression data across multiple datasets. It is worth noting that our approach discovered the circadian rhythmic patterns without the need for the sample’s timestamps.
Identification of plasma protein panels for detection of cognitive decline in MCI and AD by LC‐MS/MS
Authors: Inoue Makoto , Ito Hitomi , Liu Shan , Suzuki Hideaki , Akatsu Hiroyasu , Matsukawa Noriyuki , Asada Takashi , Arai Tetsuaki , Uchida Kazuhiko
Published: December 2021

Background

For the prevention of dementia, noninvasive screening methods which detect the signs of cognitive decline before clinical symptom occurs are needed. We previously reported blood‐based composite marker for mild cognitive impairment (MCI) and Alzheimer's disease (AD) consisting of apoA1, TTR, and C3. A combination of blood proteins could be a promising biomarker for monitoring the progression of cognitive decline from early stages of the disease. Here, we developed LC‐MS/MS‐based blood test using plasma proteins for MCI and AD to explore accurate and practical screening of the disease.

Method

We constructed a robust and reproducible LC‐MS/MS blood test system equipped with MRM to quantify 45 major plasma proteins with relatively high amounts using isotope‐labeled synthetic peptide. These plasma protein levels from 192 cases (NDC: 58, MCI: 71, AD: 63) were determined. Multinomial regression and ROC analyses were performed to identify the combination of the plasma protein panels that could discriminate NDC vs. MCI and/or AD.

Result

We found eight interpretable protein biomarker candidates in plasma for MCI and AD, which were related to innate immunity, coagulation pathways, lipid metabolism, and nutrition. Some of them are involved in the neurovascular unit injury. The optimal combination of these proteins and the coefficients of the logistic models revealed different clinical potential between male and female. In the model discriminating cognitive impairment from NDC, the AUC values of the ROC analysis were 0.82 and 0.72 for male and female, respectively. Furthermore, we constructed composite scores optimized for male and female using these plasma protein panels, and they had a significant correlation with severity of the cognitive decline determined by clinical manifestation.

Conclusion

LC‐MS‐based plasma protein panels interpretable for pathophysiology of AD detect signs of cognitive decline and progression of the disease.
The relationship between regional amyloid deposition and executive function decline in adults with Down syndrome
Authors: Hom Christy , Taylor Lisa , Mapstone Mark , Rosas H. Diana , Silverman Wayne , Krinsky‐McHale Sharon J , Pulsifer Margaret , Lai Florence , Schupf Nicole , Lott Ira T , Keator David
Published: December 2021

Background

An increase in global deposition of amyloid is known to be related to declines in a variety of cognitive domains among people with Down syndrome (DS). Less known is the correspondence between increased regional amyloid load and declines in specific functions. Since a decline in frontal lobe functions (e.g., attention, inhibitory control, shifting, motivation) is considered by many to be a key early indicator of AD dementia in adults with DS, the current study aims to identify regional amyloid changes that are associated with executive function (EF) decline in both pre‐symptomatic and symptomatic adults with DS.

Method

Longitudinal data from participants of the Biomarkers of Alzheimer’s Disease in Adults with Down Syndrome (ADDS) consortium, at all stages of AD (pre‐clinical, prodromal, and clinical dementia), were examined. Forty‐two participants received amyloid PET and MRI scans and extensive neuropsychological testing of select cognitive functions at two time points, approximately 16 months apart. Changes in amyloid accumulation in the anterior and posterior cingulate, frontal lobe, superior temporal lobe, and parietal lobe were hypothesized to be related to performance on three measures of EF: Rapid Assessment of Developmental Disabilities (RADD) Digit Span Forward and Stroop Cats and Dogs Naming and Switching. PET data were co‐registered with T1‐weighted MRIs, converted to SUVR units using the cerebellum cortex reference region, and spatially normalized using a DS MRI template in MNI space. We modeled relationships between amyloid SUVR and EF using multiple regression in SPM12 with covariates accounting for time difference between the scans and neurocognitive assessment acquisition and sex.

Results

Consistent with our hypothesis, we found clear associations between increased amyloid deposition and decline in EF in people with DS in approximately the same regions as found in neurotypical populations without AD (Figure 1). Frontal lobe amyloid deposition disrupts dorsal and ventral attention network processes.

Conclusions

We found amyloid deposition in specific functional networks correspond to EF decline in a population with lifelong amyloid production and cognitive impairments. These findings bring us one step closer to validating biomarkers of early AD in DS.
Analysis and proposal of healthcare‐related applications for the elderly
Authors: Lee Hey Sig , Park Hae Yean
Published: December 2021

Background

Trend analysis and discussion of existing elderly health‐related application studies are essential for elderly health care. Therefore, in this study, the trend of research on elderly health‐related applications is to be identified, classified and analyzed for the form, method, and purpose of the application.

Method

In this study, ten related studies were selected by searching the literature for the last five years from January 2015 to July 2020 to analyze trends in health‐related applications for the elderly, and the applications in the selected studies were divided into type, method and purpose.

Result

There were three types of applications: mobile phone, tablet PC, and computer and were three methods of applications: Direct Control‐Direct Information, Indirect Control‐Indirect Information, Direct Control‐Indirect Information and were four purposes of applications: cognitive health, physical health, mental health, lifestyle education.

Conclusion

Through this study, we can grasp information and trends on the application related to health for the elderly, and it is expected to be used as a basis for research on the long‐term effects of the application related to health for the elderly.
Outpatient cognitive therapy can change the course of dementia irrespective of etiology
Authors: Kumar Suresh , Shah Shalin , Chalamalasetty Prasanth , Kumar Aryan
Published: December 2021

Introduction

Neuroplasticity can only occur in an ideal body condition and establish a new synaptic connection with repeated stimulations in weak cognitive domains or circuits.

Method

A Two‐phase study was planned as a course of memory loss treatment in an outpatient clinic for a period of 3 years. 49 of 72 acquired brain injury and dementia patients completed X≥14 sessions of cognitive therapy intervention within the period of 2‐4 months. Patients selected for intervention had mild severe memory loss on MoCA Score [(9‐24)/30]. The first phase of intervention was the correction of nutraceutical status and sleep optimization. The second phase of the intervention was individualized cognitive therapy (CT) by trained cognitive therapists after the Digital Mobile Assessment of Cognitive test (DMAC) was given before and after an intervention. The domains included visual, auditory, delayed recall, attention, executive, number recall, disinhibition, language, and working memory.

Results

Statistical analysis of n‐49 with confidence interval 95%, series paired t‐tests showed in the post‐intervention group, on average, scores were higher as follows: Visual domain 4.89% to 13.74% (p < 0.001), Auditory domain 8.35% to 19.72% (p < 0.001), Delayed recall 21.34% to 33.95% (p < 0.001), Disinhibition Frontal domain 6.89% to 21.80% (p < 0.001), Attention domain 9.33%, 26.12% (p < 0.001 ), Executive domain 9.81%, 23.06% ( p < 0.001), Number domain 5.22% to 17.91% (p < 0.001), and Working memory 2.96%, 29.85% (p = 0.01).

Discussion

Dr. Eric Kandel, Nobel Laureate, showed that damaged neurons can synapse after repeated neuron stimulation. Physical therapy is a standard of practice after acquired brain injury, but cognitive impairment evaluation is often ignored. The systematic approach to body optimization for learning and cognitive therapy can change the course of cognitive decline in dementia or acquired brain injury.

Conclusion

The significant improvement in mild to severe dementia in short‐term memory or patients’ ability of memory retention improved 22% to 34% in the intervention group provides statistically significant evidence that a systematic approach to cognitive therapy can reverse the course of cognitive decline.
Multimodal brain imaging demonstrates that both amyloid burden and glucose metabolism predict the severity of cognitive impairment in patients with Alzheimer’s disease
Authors: Atay Lutfiye Ozlem , Akdemir Umit Ozgur , Yetim Ezgi , Balci Erdem , Arsava Ethem Murat , Topcuoglu Mehmet Akif , Saka Esen
Published: December 2021

Background

The purpose of this study is to assess brain glucose metabolism and Amyloid‐β burden in patients with Alzheimer’s disease with 3 Tesla PET/MR imaging and to seek possible relation of imaging findings with the extent of cognitive impairment.

Method

45 consecutive subjects with memory complaints were evaluated with a detailed neuropsychological test battery and F18‐Fluorodeoxyglucose(FDG)‐PET/MRI and F18‐Flutemetamol‐PET/MRI scans. The imaging modalities were performed with a hybrid 3T PET / MR camera at a maximum of 7 days intervals. Images were visually evaluated by two nuclear medicine experts. The centiloid scores were calculated through amyloid standardized uptake value ratios (SUVR) for all participants and regional glucose metabolism characteristics were analyzed.

Result

The study population consisted of 30 males and 15 females with a mean age of 65.9±8.2 years. Mean MMSE was 21.7±7.2 for the overall group. Five patients had imaging features suggestive of non‐AD type of dementias and were excluded from further analyses. Visual examination of F18‐Flutemetamol PET/MRI was consistent with the Alzheimer’s disease continuum in 29 cases, 9 of them demonstrated normal glucose metabolism, whereas 20 remaining cases showed F18‐FDG‐PET/MRI patterns characteristic to Alzheimer’s disease (hypometabolism in parieto‐temporal cortices and/or posterior cingulate cortex). In bivariate analysis, MMSE was positively correlated with the glucose metabolism in temporal lobe and posterior cingulate gyrus (r= 0.382, p=0.020; r=0.330, p=0.046; respectively), additionally, a significant negative correlation was observed between MMSE and amyloid burden designated by the centiloid score (r=‐0.461, p=0.004). Memory performance tested by Enhanced Cued Recall (ECR) was also positively associated with the glucose metabolism in posterior cingulate gyrus (r= 0.446, p=0.006), and negatively associated with the centiloid value (r= ‐0.458, p=0.005). The relationship between the ECR test and the centiloid value persisted when adjusted for age, gender, and year of education (β=‐0.121, p=0.021) in multivariate models.

Conclusion

General cognitive ability and memory were predicted by imaging markers of regional glucose metabolism and amyloid deposition in this study population with early‐stage Alzheimer’s disease. Further research should investigate the predictive value of those imaging markers for the rate of cognitive decline. Acknowledgment: We acknowledge the support of GE Health Care for the [F18]flutemetamol doses.
The impact of ICT use on feelings of loneliness and isolation during the COVID‐19 lockdown among older people
Authors: Vaccaro Roberta , Rolandi Elena , Colombo Mauro , Abbondanza Simona , Pettinato Laura , Poloni Tino Emanuele , Davin Annalisa , Guaita Antonio
Published: December 2021

Background

Older adults are at risk of psychological consequences along home segregation during COVID‐19 pandemic. Information Communication Technologies (ICTs) are crucial in such context even among older people. Aim: to explore the impact of being ICTusers on loneliness and ICTs use among older adults from pre to lockdown period.

Methods

Data were extracted from the fourth follow‐up (2018) of the InveCe.Ab, a multidimensional population‐based study (NCT01345110) on 70‐75 older people living in Abbiategrasso (Milan, Lombardy) at baseline (2009). Sixty‐six of them were trained for SNS use in 2019, as a part of the ANS‐SE study (NCT04242628). A telephone interview was administered during the lockdown period (March‐May 2020), collecting information on self‐perceived loneliness measured by the 3‐item UCLA loneliness scale and ICT use [smartphones, computers, internet and Social Network Sites (SNSs)]. Participants in the pre‐lockdown assessment reporting use of any ICT were defined as ICTusers. Cross‐sectional differences between ICTusers and non‐users were explored using Independent Sample t‐test or Chi‐square test. Analysis of covariance (ANCOVA) was applied to compare the long‐term effect of being ICTusers and non‐users on loneliness change (UCLA 3‐item total and subscales) and ICT use change, including the pre‐lockdown measures and being trained for SNSs use as covariates, followed by post‐hoc comparisons.

Results

Pre‐lockdown participants with ICT use data available were 623 (163 ICT users, 460 non‐users). Table 1 shows that ICTusers were mostly men, more educated, showed fewer depressive symptoms (GDS) and higher global cognition (MMSE) than ICTnon‐users. ICTusers felt less total loneliness, fewer feelings of a lack of companionship and isolation from others than ICTnon‐users. Pre‐lockdown ICT use was on average 2.11 (DS 1.05). Longitudinal significant difference emerged between the two groups on total loneliness, with ICTusers (n=130), showing a decrease (mean difference (SE): ‐0.382 (0.179); 95% CI: ‐0.733, ‐0.030; p=0.033) compared to non‐users (n=296). ICTusers (n=130), reported fewer feelings of isolation (mean difference (SE): ‐0.213 (0.068); 95% CI: ‐0.348, ‐0.079; p=0.002) than non‐users (n=300).

Conclusions

During the COVID‐19 lockdown, former ICTusers were protected against feelings of loneliness and isolation. The ICT use did not change in both groups.
Effects of coach robot pepper versus tablet training on psychosocial and physical outcomes of persons with dementia: A mixed‐methods study
Authors: Schüssler Sandra , Zuschnegg Julia , Paletta Lucas , Lodron Gerald , Steiner Josef , Pansy‐Resch Sandra , Prodromou Dimitrios , Brunsch Sebastian , Carnevale Lorenzo , Orgel Thomas , Schneeberger Michael , Russegger Silvia , Fellner Maria , Lammer Lara , Holter Magdalena
Published: December 2021

Background

The evidence of social robots for people with dementia (PwD) living at home is unclear. The aim was to explore the effects of Coach Pepper (socially assistive humanoid robot system “AMIGO” combined with external tablet‐based training) versus an exclusively tablet‐based training on quality of life, motivation, cognition, mobility, care dependency, depression, and neuropsychiatric symptoms, as well as the user experience with Coach Pepper.

Methods

The study (2019‐2020) includes a randomized controlled trial with complementary interviews using content analysis. The intervention group (16 PwD) received Coach Pepper and the control group (16 PwD) an exclusively tablet‐based training for three weeks. Data were collected using standardized questionnaires (AES, MOCA, DEMQOL, PAS, TUG, GDS, NPI) and interviews.

Results

In both groups, PwD were >80 years old and mainly female. The mild stage of Alzheimer's was predominant in both groups. The comparison of quality of life (DEMQOL questionnaire) between the groups showed a significantly greater increase in the Coach Pepper group (X̅: 5.48 vs. ‐0.31; med: 4 vs. 2 points, p = 0.0226). Furthermore, global quality of life increased significantly in the Coach Pepper group (X̅: 0.4 vs. ‐0.2; med: 1.0 vs. 0.0 points; p = 0.013). All other outcomes did not differ significantly. Main qualitative results: Attitude/feelings ‐ PwD reacted mainly positively to Pepper. The PwD were generally not afraid of Pepper and did not feel repulsed. They found Pepper nice/pleasant and funny. Communication, social contacts ‐ Pepper was received well and integrated as a family member. His presence was not disturbing, more an enrichment. PwD regarded Pepper as a friend, child and contact person. He promoted communication in PwD. The life of PwD “bloomed” and they bonded with Pepper, which caused feelings of sadness after Pepper moved out. Meaningful activities‐ music and dance activities stimulated PwD particularly positively.

Conclusion

Coach Pepper significantly increased the quality of life of the PwD in the robot group. As the additional qualitative results demonstrate, this increase can be attributed in particular to the promotion of communication and social contacts by Pepper. Further research should focus on the increase of Pepper’s communication skills and program content.
A convolutional neural network algorithm for step and gait bout estimation from wristband accelerometry
Authors: Peraza Luis R. , Kinnunen Kirsi M. , Joules Richard , Wolz Robin
Published: December 2021

Background

Walking depends on an intricate interplay between cognitive and motor functions that can be impaired by neurodegeneration. Recent developments on the use of wearable sensors permit the measurement of multiple gait markers to establish their association with symptoms of neurodegeneration. To estimate gait markers, accurate algorithms have been developed for sensors worn around the trunk (e.g., waist) or on lower limbs. However, there has been limited research to develop gait algorithms for wristband accelerometry, despite their superior wear compliance compared to other body‐worn sensors. Our work aims to investigate the feasibility of gait metrics estimated from wrist‐worn accelerometry devices.

Method

Healthy adults (N=26) were recruited in a multiactivity study which also included a 25‐feet walking exercise along a corridor. Participants wore a lumbar wearable sensor (AX3, Axivity) and a wristband sensor on the non‐dominant hand (GENEActiv, Activinsights). Both devices were mechanically synchronised before and after each study session. Steps were detected and labelled with a heel‐impact detection algorithm applied on the lumbar sensor accelerometry data. Posterior visual inspection was implemented to correct for non‐steps or missing steps. Step labels were posteriorly used to train a convolutional neural network (CNN) algorithm to detect individual steps from the wristband device as well as standing and walking segments. Algorithm performance was assessed with a leave‐one‐subject‐out (LOSO) validation procedure.

Result

The LOSO validation resulted in an average global accuracy of 88% (95% confidence interval, CI: 87 – 90%) for the three labels of standing, walking, and steps. For the detection of individual steps, the percentage of absolute error was 6.5% (95% CI: 4.9 ‐ 8.0%), or an error of 6.5 steps per 100. The heel impact time error detection showed a mean delay of +9.7 msecs (95% CI: ‐2.2 ‐ 21.7 msecs).

Conclusion

Our investigation shows that it is feasible to assess gait from wristband devices using CNNs with high accuracy and an acceptable level of model generalisation. Our future work will focus on further improvements to our gait models, and on transferring the trained CNN models to estimate gait in populations affected by neurodegenerative conditions such as different forms of dementia, Parkinsonian disorders, and Huntington’s disease.
Association of air quality reduction with incident dementia: Effects of natural course and hypothetical air pollutant interventions using g‐computation
Authors: Letellier Noemie , Gutierrez Laure‐Anne , Berr Claudine , Mortamais Marion , Benmarhnia Tarik
Published: December 2021

Background

The benefits of air quality improvement on the burden of neurological disorders could be substantial given the emerging evidence regarding the role of air pollution on dementia incidence. However, none evidence exists about the impact of air pollution reduction on incidence of dementia. The aim of this study is to quantify how observed reduction in PM2.5 concentration leads to dementia‐incidence benefits and simulate the benefits of hypothetical air quality improvement interventions on the reduction of dementia incidence.

Methods

Among the French Three‐City Cohort (12 years of follow‐up), dementia diagnoses were made using DSM‐IV criteria and validated by an adjudication committee. Exposure to PM2.5 was estimated using Land Use Regression models. We performed multi‐level Cox proportional and Aalen additive hazard regression models to assess the effect of observed PM2.5 reduction on dementia risk. Then, we used a parametric g‐computation approach to quantify the effects of various hypothetical interventions to reduce PM2.5 exposure on dementia risk.

Results

Among 7051 participants (median age: 73), the median PM2.5 reduction between 1990 and 2000, 10 years prior to inclusion, was 12.2 (µg/m3). Such reduction reduced the risk of all‐type of dementia (hazard ratio (HR) 0.85, 95% confidence interval (CI):0.76‐0.95) and Alzheimer's disease (HR 0.83, 95%CI:0.72‐0.94). Approximately 197 less cases of all type of dementia per 100 000 persons and year could be attributed to PM2.5 reduction. Using g‐computation, we quantified the expected number of prevented dementia cases under different hypothetical interventions. For example, for compliance with a hypothetical reduction of more than 13.10 µg/m3 (reduction observed in the city of Montpellier), the rate difference was ‐0.33 (95%CI, −0.51 to −0.15).

Conclusion

These findings highlight the possible substantial benefits of reducing air pollution in the prevention of dementia.
Very long term visit‐to‐visit blood pressure variability and the risk of dementia in the Adult Changes in Thought study
Authors: den Brok Melina GHE , van Dalen Jan Willem , Marcum Zachary , van Middelaar Tessa , Hilkens Nina , Klijn Catharina JM , van Gool Willem A , Crane Paul K , Larson Eric B , Richard Edo
Published: December 2021

Background

High visit‐to‐visit blood pressure variability (BPV) is associated with an increased risk of cardiovascular disease. However, for incident dementia, conflicting results are reported. Our objective was to assess the association of very long‐term visit‐to‐visit BPV and the risk of all‐cause dementia in community‐dwelling individuals.

Method

Community‐dwelling individuals aged 65 years or older and free from dementia were randomly sampled from 1994 onwards from Kaiser Permanente Washington (KPW), Seattle, USA, and included in the Adult Changes in Thought (ACT) study. After enrollment, participants were followed‐up biannually. We retrospectively collected yearly data on blood pressure measurements and medical history from the age of 50 up to recruitment into the ACT study, through KPW electronic databases. Visit‐to‐visit BPV was defined as coefficient of variation (SD/mean*100) calculated with systolic blood pressure measurements. Dementia was diagnosed by an expert panel based on DSM‐IV and NINCDS‐ADRDA criteria. We used Cox regression adjusted for sex, blood pressure trend, antihypertensive medication use and cardiovascular risk factors. Subgroup analyses were performed for midlife (50‐64) and later life (≥65).

Result

We included 1174 individuals with a median age of 78 years [IQR=72‐83] at inclusion in the ACT study. Systolic blood pressure measurements (mean=27.9, SD=8.5, range: 2‐50) were collected over 2 to 54 years (mean=31.8, SD=9.4), and 483 (41.1%) individuals developed dementia. There was no significant association between very long term visit‐to‐visit BPV (mean=12.15; SD=2.67) and incident all‐cause dementia (HR=0.98; 95%CI=0.94‐1.02). Competing risk of death analyses (combined outcome dementia/death) showed a dementia/mortality risk reduction of 4% per point visit‐to‐visit BPV increase (HR=0.96; 95%CI=0.94‐0.99). The associations were similar for visit‐to‐visit BPV in later life (dementia: HR=0.99; 95%CI=0.95‐1.02, dementia/death: HR=0.96; 95%CI=0.93‐0.99). Visit‐to‐visit BPV in midlife was not associated with incident dementia (dementia: HR=0.99; 95%CI=0.96‐1.02, dementia/death: HR=1.01; 95%CI=0.99‐1.02).

Conclusion

In our sample, higher very long‐term visit‐to‐visit BPV is associated with lower incident all‐cause dementia risks. This association might be stronger in later life than in midlife.
Orthostatic hypertension is associated with lower plasma Aβ42/Aβ40 ratio: The Multidomain Alzheimer Preventive Trial (MAPT)
Authors: Rouch Laure , Rolland Yves , Hanon Olivier , Vidal Jean‐Sébastien , Andrieu Sandrine , Barreto Philipe de Souto , Vellas Bruno
Published: December 2021

Background

Orthostatic hypertension (OHYPER), an emerging hemodynamic cardiovascular risk factor, is associated with cardiovascular events and mortality. Recent findings indicated that it could be an important risk factor for cognitive decline and dementia, including Alzheimer’s disease (AD). We aimed to assess the association between OHYPER and low plasma Aβ42/Aβ40 ratio, a surrogate biomarker for brain amyloidosis, associated with greater risk of mild cognitive impairment (MCI) and AD.

Method

We included 483 non‐demented community‐dwelling participants aged ≥ 70 years from the Multidomain Alzheimer Preventive Trial (MAPT). OHYPER was assessed at baseline and defined as an increase of at least 20 mmHg in systolic blood pressure (BP) and/or 10 mmHg in diastolic BP after standing. Plasma Aβ42 and Aβ40 were measured at 12 months, using an immunoprecipitation and liquid chromatography‐mass spectrometry assay. Low plasma Aβ42/Aβ40 ratio was defined as ≤ 0.107. Logistic regression models were used to assess the association between OHYPER and low plasma Aβ42/Aβ40 ratio.

Result

Of 483 participants (mean age 76 years, 59% female), 113 (23.6%) had OHYPER and 161 (33.3%) low plasma Aβ42/Aβ40 ratio. OHYPER was associated with low plasma Aβ42/Aβ40 ratio (OR = 1.58, 95% CI [1.02‐2.44]) in unadjusted models. Adjustment for age, sex, education, MAPT randomization group, lying BP, antihypertensive drug use, MCI, and presence of 1 or 2 ApoE ε4 alleles did not change the results (OR = 1.67, 95% CI [1.02‐2.72]). Sensitivity analyses using the 25th percentile of plasma Aβ42/Aβ40 ratio (≤ 0.103) as an alternative cutoff and long‐term OHYPER (at least two‐thirds of visits over 12 months) reported consistent findings.

Conclusion

OHYPER was associated with lower plasma Aβ42/Aβ40 ratio in community‐dwelling older adults, even after accounting for potential confounders. Monitoring OHYPER may have clinical utility for identifying patients who are at risk for cognitive decline, AD or in the preclinical stages of the disease.
Early detection of frontotemporal dementia (EDoF): A digital biomarker study
Authors: Convery Rhian S , Russell Lucy L , Bocchetta Martina , Rohrer Jonathan D
Published: December 2021

Background

With the commencement of clinical trials in frontotemporal dementia (FTD), robust biomarkers that can detect the earliest signs of the disease and also measure treatment effect, are essential. Pen and paper assessments are laborious, administered infrequently, and can rely on subjective reporting. Using digital devices allows for more frequent, often continuous, assessment from home, whilst producing a wealth of objective data. The Early Detection of Frontotemporal dementia (EDoF) study aims to develop a series of digital measures that may be useful for the diagnosis of FTD and for outcome measures in trials.

Method

The EDoF study includes: a computerised cognitive battery, a mobile eye tracking device, a novel app that passively measures cognitive function by monitoring smartphone metadata, speech and language analysis using machine learning algorithms, actigraphy, and gait analysis. These measures are being validated in a large control population before being tested in symptomatic and presymptomatic genetic FTD within the Genetic FTD Initiative (GENFI) study.

Result

We are currently recruiting participants to the initial arms of the study, with over 1,300 healthy controls having already completed the computerized cognitive battery. The mobile eye tracking device measures eye movement abnormalities but also uses instructionless eye movement tasks to measure executive function and social cognition. Pilot eye tracking data shows abnormalities of these tasks in symptomatic FTD, and also for antisaccadic eye movements in presymptomatic FTD. Normative data for all of the measures will be generated helping to assess construct validity and retest reliability.

Conclusion

EDoF is the first study aiming to use a comprehensive set of digital measures to detect early FTD. It may also prove useful for home monitoring within future therapeutic trials of FTD.
TNF inhibitors for the prevention of Alzheimer’s disease: Preliminary findings from the rheumatoid arthritis medication and memory study (RESIST)
Authors: McDowell Bethany , Holmes Clive , Edwards Christopher J , Cardwell Christopher , McHenry Michelle , Meenagh Gary , McGuinness Bernadette
Published: December 2021

Background

A raised level of serum TNFα observed in patients with Alzheimer’s disease has been associated with an increased rate of neurodegeneration and risk of conversion from mild cognitive impairment (MCI) to AD dementia. This led to the hypothesis that reduction in peripheral TNFα via TNF inhibitors (TNFi) may reduce the rate of neurodegeneration and may protect against development of AD.

Method

The rheumatoid arthritis medication and memory study (RESIST) is an 18‐month observational study which aims to compare the rate of cognitive decline between TNFi and conventional synthetic disease modifying anti‐rheumatic drugs (csDMARDs) in patients with both rheumatoid arthritis (RA) and MCI. Participants ≥ 55 years of age were recruited from rheumatology clinics in both Northern Ireland and Southampton and were cognitively assessed using the Free and Cued Selective Reminding Test (FCSRT) and Montreal Cognitive Assessment (MoCA). At the time of analysis n=130 participants had completed a 6‐month assessment and n=69 had completed a 12‐month assessment. ANCOVA analysis was conducted to calculate the difference in mean (and 95% CI) FCSRT and MoCA scores at both 6‐ and 12‐month timepoints between TNFi and csDMARD treatment groups, adjusting for baseline cognitive scores. Further adjustments were made for age, gender, RA disease activity and other confounding variables.

Result

There was no evidence of a difference between TNFi and csDMARD treatment in cognitive outcomes measured by FCSRT (6‐month cohort (mean difference 0.58, 95% CI ‐ 1.40, 2.56, p = 0.565); 12‐month cohort (mean difference ‐1.09, 95% CI ‐3.57, 1.38, p = 0.381)) or MoCA (6‐month cohort (mean difference ‐1.09, 95% CI ‐3.57, 1.38, p = 0.381); 12‐month cohort (mean difference ‐0.04, 95% CI ‐1.06, 0.98, p = 0.940)) after adjustment for baseline cognitive scores nor was there a difference in cognitive outcomes between treatment groups after adjustment for additional confounders.

Conclusion

This preliminary analysis found little evidence of a relationship between TNFi and better cognitive performance however analysis was limited by lack of power and short follow‐up periods. This analysis will be repeated once RESIST has ended to determine if there is any statistically significant cognitive benefit of TNFi treatment after 18‐months.
Simultaneous assessment of posture and saccadic eye movement with visual stimuli using head‐mounted display virtual reality technology in healthy older adults
Authors: Imaoka Yu , Flury Andri , de Bruin Eling Douwe
Published: December 2021

Background

Postural sway and saccadic eye movement could be potential biomarkers to diagnose Alzheimer’s disease (AD) [1, 2]. We developed a new assessment system to evaluate posture and saccadic eye movement simultaneously in healthy older adults (OA) with visual stimuli of distractors, lower contrast, and stereopsis, which are also considered to be another deficit in people with AD [3‐5]. We hypothesised that more latency and errors in saccade would be observed in the condition with visual stimuli.

Method

14 healthy older adults (71.9±4.8 years, 7 men / 7 women) joined the experiment after taking Montreal Cognitive Assessment (MoCA). The system consisted of stabilometer (GP‐5000, ANIMA Corporation, Japan) and a head‐mounted display virtual reality technology (VIVE Pro Eye, HTC Corporation, Taiwan). We measured both posture and eye movement simultaneously in the following test conditions: #1‐2) eyes‐open and closed without VR, #3‐4) pro‐ and anti‐saccade tests in 2D environment, and #5‐6) pro‐ and anti‐saccade tests in 3D environment. We developed the 2D environment for the baseline saccade measurement and 3D environment with more visual stimuli [6]. Each test took 60 seconds with 30 saccade trials.

Result

The participants achieved MoCA score of 27.5±1.6. We found significant difference in saccade latency between saccade types (mean: P < 0.001, SD: P < 0.001) but less significant difference between VR scenery (mean: P = 0.01, SD: P = 0.42). Moreover, we observed less significant difference in saccade error rate between saccade types (P = 0.07) and between VR scenery (P > 0.77). We did not see significant difference in postural sway (P > 0.05).

Conclusion

The results may imply that the healthy OA had sufficient attentional resources to both conduct the saccade tasks and maintain their posture in the designed VR environment with visual stimuli. Further research is required to evaluate the difference between OA with and without cognitive impairment. References: 1. Bahureksa, L., et al. (2017) 2. Wilcockson, T.D.W., et al. (2019) 3. Rizzo, M., et al. (2000) 4. Lee, C.N., et al. (2015) 5. Cunha, J.P., et al. (2016) 6. Imaoka, Y., et al. (2020)
Trial readiness amongst EPAD longitudinal cohort study participants: Insights from the SPEAR study
Authors: Brenman Natassia F. , Milne Richard , Brayne Carol
Published: December 2021

Background

SPEAR (Study of Participant Experience of Alzheimer’s disease Research) was a sub‐study of work on the Ethical, Legal and Social Implications of the European Prevention of Alzheimer’s Dementia (EPAD) project. The EPAD Longitudinal Cohort Study (LCS) aimed to generate a detailed picture of biological and cognitive change over time, and to build a ‘readiness cohort’ to recruit eligible and willing participants into clinical trials. This poster presents findings about the willingness of cohort participants to participate in a future clinical trial.

Method

A mixed‐method study was conducted with members of the EPAD Longitudinal Cohort Study (LCS) to explore motivations to participate, study experience and likely future participation in an Alzheimer’s prevention trial. A questionnaire was completed by 101 participants and 7 study partners from 4 EPAD sites across the UK. In‐depth qualitative interviews were conducted with 25 EPAD participants and study visits observed from the same 4 sites.

Result

Over half of participants would consider participating in a clinical trial at the time of data collection. Almost none reported that they would “never” participate. The timing, location and duration of trials were important in how likely they would be to participate. The qualitative findings revealed a range of tentative attitudes towards the prospect of being recruited to a clinical trial, including feeling “morally obliged to continue” or indicating “I don’t want a drug,” should they agree to participate. Some said changes in their memory or cognition may also influence future decisions.

Conclusion

Whilst we saw high levels of willingness to participate in a clinical trial, these data highlight the importance of understanding how motivations, willingness, and expectations for trial participation may change over time. This supports the use of a staged consent model such as that adopted by EPAD. Qualitative research is needed to understand underlying reasons for participants’ trial readiness to identify any ethical issues in the recruitment of future trial participants.
The effects of age and hypertension on cerebral small‐vessel disease differ between men and women at midlife: The PREVENT Dementia study
Authors: Low Audrey , Prats‐Sedano Maria , Stefaniak James D , Dounavi Maria‐Eleni , McKiernan Elizabeth , Carter Stephen F , Mak Elijah , Su Li , Muñiz‐Terrera Graciela , Ritchie Karen , Ritchie Craig W , Markus Hugh S , O'Brien John T
Published: December 2021

Background

Sex differences exist in the prevalence, prognosis, and clinical manifestation of cerebral small vessel disease (SVD) and dementia. Given the role of SVD in cognitive impairment – both directly and through accelerating neurodegenerative pathology – understanding sex differences in SVD risk factors could inform targeted intervention strategies. In this longitudinal study, we examined sex differences in the effects of age and hypertension on SVD at midlife.

Method

185 cognitively‐healthy midlife adults underwent 3T MRI at baseline and two‐year follow‐up. SVD markers were white matter hyperintensities (WMH) volume, enlarged perivascular spaces, microbleeds, lacunes, and global SVD burden (composite score of all four SVD markers). Piecewise linear regression analysis estimated change‐points in age, beyond which WMH accelerates. To examine sex as a moderator of age and hypertension on SVD cross‐sectionally, interaction analysis was conducted in general linear models, adjusting for age and education. To assess interactions on longitudinal SVD progression, linear mixed effects models were fitted, adjusting for the same covariates and random intercept of subjects.

Result

Males were twice as likely to have hypertension compared to females (males:53.8%, females:26.4%, X
2=7.97, p=.005). Interaction analysis demonstrated that the effect of hypertension on SVD was amplified in females, compared to males, both cross‐sectionally (WMH: t=2.42, p=.017) and longitudinally (WMH progression: t=3.37, p<.001; new microbleeds: t=2.57, p=.011) (Fig 1). Findings remained consistent when additionally controlling for antihypertensive medication. In terms of age, piecewise linear regression estimated a WMH change‐point at age 50.2 (SE=3.2) in the whole sample, 50.6 years (SE=3.8) in males, but was undetectable in females (Fig 2). Sex*age interaction demonstrated that the effect of age on global SVD burden was amplified in males compared to females (t=‐2.43, p=.016) (Fig 3). Sex*age*hypertension interaction showed that hypertension intensified the effect of age on global SVD burden in males but not females (t=‐2.67, p=.008), for whom hypertension was a stronger predictor than age.

Conclusion

Older men (especially those with hypertension) and women with hypertension (regardless of age) were at greatest risk of SVD. Our findings highlight the importance of hypertension management as early as midlife in relation to SVD, but suggest that this may be especially effective for women.
Divergent brain connectivity patterns in relation to cognition in Alzheimer’s disease and frontotemporal dementia
Authors: Pini Lorenzo , de Lange Siemon , Pizzini Francesca B , Galazzo Ilaria Boscolo , Manenti Rosa , van den Heuvel Martijn , Pievani Michela
Published: December 2021

Background

Divergent functional connectivity (FC) abnormalities between networks linked with core cognitive deficits have been reported in Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD), the default mode (DMN) and ventral‐attention (VAN), respectively. As cognition relies on the balance between brain networks, we investigated the coupling patterns between different cognitive domains and networks.

Method

Twenty‐one bvFTD (age: 71±10), 22 AD (age: 72±6) and 20 healthy controls (HC, age: 72±6) underwent cognitive evaluation and 3T resting‐state functional MRI (rsfMRI). We investigated the relationship between memory, language, executive, visuospatial and emotion recognition with FC of cognitive networks: DMN, VAN, frontoparietal (FPN), and dorsal‐attention (DAN). The visual network (VIS) was included as a control network. FC was assessed with a connectome analysis. Cortical parcels were defined using a high‐resolution structural MRI parcellation. Connectivity matrices were created assessing correlations between parcels within each functional network (Yeo 2011 parcellation). Correlation values were thresholded to retain positive values. FC and cognitive differences between groups were assessed with Kruskal‐Wallis test, Spearman’s correlation was used to assess relationships between FC and cognition.

Result

Compared to HC, AD and bvFTD showed impairment in all cognitive domains (p<0.001), and bvFTD scored worse than AD in emotion recognition (p=0.013). At the network level, AD showed reduced FC in the DMN, FPN and DAN (p<0.05) and bvFTD in the VAN (p<0.05) compared to HC. In bvFTD, reduced VAN connectivity was associated with executive deficits (r=0.444; p=0.038). In AD, reduced FPN connectivity was associated with language deficits (r=0.441; p=0.04), while the opposite pattern was observed in bvFTD (r=‐0.468; p=0.028). Moreover, in AD patients DMN connectivity was negatively associated with executive deficits (r=‐0.56; p=0.007). A significant interaction was detected between AD and bvFTD for the following cognitive‐network associations: VAN‐executive: p=0.027; FPN‐language: p=0.015. No significant association was detected between DMN‐memory in AD or VAN‐emotion recognition in bvFTD (p>0.06), nor between cognition and VIS (p>0.09 for all associations).

Conclusion

These results suggest a divergent FC‐cognitive pattern between AD and bvFTD in attention/executive networks/functions. We speculate that, as pathology spreads, disease‐specific symptom‐network coupling might weaken, and aberrant patterns may emerge in other domains.