bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of soluble epoxide hydrolase inhibition in a rat model of Alzheimer’s disease
Authors: Di Lucente Jacopo , Freitas Hercules R , Wagner Karen M , Hammock Bruce D. , Maezawa Izumi , Jin Lee‐Way
Published: December 2021

Background

Epoxy fatty acids (EpFAs) are cytochrome P450‐dependent derivatives of PUFAs with potent anti‐inflammatory, pro‐resolving properties. However, their activities are extremely short‐lived as soluble epoxide hydrolase (sEH) quickly converts EpFAs to pro‐inflammatory diols. Here we test the hypothesis that inhibition of sEH is a potential therapeutic approach for Alzheimer’s disease (AD) via increasing the anti‐inflammatory actions of EpFAs in the brain.

Method

The functional expression of sEH in the TgF344‐AD model of AD and the human AD brain tissue samples, compared with control brain samples, was studied using qPCR, immunohistochemistry, and Western blotting. An orally available specific sEH inhibitor called 1770 was investigated for its effects on rectifying AD‐like deficits by treating 12 months old TgF344‐AD mice with 3 mg/kg/day 1770 via drinking water for 4 months and evaluating them by neurobehavioral, electrophysiological, and neuropathological assessments.

Result

sEH was found to be overexpressed in both TgF344‐AD rat and human AD brains. All assessments conducted in the open field maze showed no significant differences between groups. We observed sensorimotor gating deficits in TgF344‐AD rats using acoustic startle response and prepulse inhibition task, which were reversed by 1770 treatment. We further observed deficits in novel object recognition and step‐through passive avoidance tests in TgF344‐AD rats, which were also mitigated by 1770 treatment. Consistent with enhanced memory performance, 1770 treatment rectified hippocampal long‐term potentiation deficits seen in TgF344‐AD rats. Immunohistochemical stains showed that 1770 treatment reduced microglial activation and Aβ amyloid load. Transcriptomics profiling is being conducted to further analyze mechanisms induced by 1770.

Conclusion

Based on our rat model data and previous data using cell and mouse models, sEH inhibition is a promising therapeutic approach to AD. Investigating the pathways for EpFAs production, degradation, and signaling may provide exciting new mechanisms and therapeutic targets for chronic neuroinflammatory conditions such as AD.
Adjustment to test, risk and diagnostic disclosures in people with mild cognitive impairment: An observational cohort study
Authors: Saunders Stina , Muñiz‐Terrera Graciela , Russ Tom C , Ritchie Craig W.
Published: December 2021

Background

Mild cognitive impairment (MCI) is a condition with slight decline in cognition, but unaffected daily functioning. Given its uncertain prognosis, communicating this in clinical consultations with patients is crucial. Our aim was to understand the impact of clinical risk reporting to individuals with newly identified MCI, focusing on changes in cognition, anxiety, psychological well‐being and adjustment to illness in the short and long term.

Method

This is a longitudinal mixed methods study. Participants who were referred to a memory clinic with a suspected MCI were recruited from across South‐East Scotland. Baseline assessments (June 2018‐July 2019) were conducted before the MCI risk disclosure. Follow up assessments started after individuals were disclosed of memory assessment results and were carried out over two years (completed by May 2021 due to COVID‐19 restrictions). The primary outcome measures are neuropsychological assessment (RBANS), anxiety assessment (STAI) and results from semi‐structured interviews.

Result

There are 63 individuals recruited (men = 25, 40%; women = 38, 60%); average age 77 years, SD=6.76; average years of education 13 (mode 10). At baseline, the mean RBANS score was 87 (SD=15.79); STAI score 81 (SD=20.59). A higher RBANS score at baseline was predicted by more years of education and higher score in ‘Attitude toward present treatment & doctors.’ Being identified as having MCI was predicted by higher perceived deficits and feelings of depression and worry. Longitudinal analyses of adjustment to MCI will be presented at the conference. Initial results of the interviews show that the concept of MCI is perceived with mixed feelings, with the immediate response to disclosure more positive and as time goes on, the initial perception shifting.

Conclusion

Baseline RBANS results are consistent with other research on the same clinical population. This study gives empirical evidence on the impact of being informed of test results at the pre‐dementia or early dementia stages where future prognosis is uncertain. The longitudinal data will be used to identify modifiable risk factors for adjusting to MCI disclosure well or less well.
Investigating the relationship of drugs prescribed to treat hypertension and hypercholesterolemia with disease progression in Alzheimer’s disease and related dementias
Authors: Sadoo Annie B , Davies Neil M , Kehoe Patrick G , Martin Richard M , Walker Venexia M
Published: December 2021

Background

Dementia is at present incurable. It is seen in a range of neurodegenerative diseases, the most common being Alzheimer’s disease (AD). The debilitating neurocognitive deficits develop over time and available treatments have limited effectiveness. It is of paramount and economic concern to identify new and safe possibilities for treatment. Current treatments are aimed at managing symptoms, but do not address the underlying cause of disease. Existing medications work to minimise toxicity caused from breakdown of neurons and brain connections, and preserve neurochemical levels important in cognitive function. Hypertension and hypercholesterolemia, have been linked with increased risk of developing AD. Antihypertensive drugs may protect against AD and lead to reduced disease progression through decreasing neuropathological mechanisms. Statins treat high cholesterol. High cholesterol relates with elevated levels of β‐amyloid protein, an accumulation in brain tissue leads to formation of amyloid plaques, toxic to neurons. Cholesterol‐lowering medication lowers amyloid plaques in brain tissue.

Method

Data will be obtained from the Clinical Practice Research Datalink (CPRD), an ongoing database of UK primary care data. The determined sample population, estimated at 105 471 patients, will be divided according to their prescribed medications. Data on treatments will be compared for each group against outcomes such as death and hospitalisation due to AD and related dementias. Potential confounders will be adjusted for in the regression model. Associations between the exposures and outcomes will be assessed through multivariable regression analyses; multivariable Cox regression analysis for assessing survival rate; and marginal structural models to control for treatment switching. Appropriate statistical analysis methods will also be applied to account for other biases, including: propensity score regression to minimise bias due to working with data from non‐randomised comparison of treatments; multiple imputation to account for missing data; and use of appropriate inclusion criteria to prevent collider bias.

Result

We will present the results at a later time.

Conclusion

This project will allow us to better understand the link between progression of neurological disorders and pharmacotherapy.
Optimizing software methods for measuring flortaucipir SUVR change over time
Authors: Schwarz Christopher G. , Therneau Terry M. , Weigand Stephen D , Gunter Jeffrey L. , Lowe Val J , Przybelski Scott A. , Senjem Matthew L. , Botha Hugo , Vemuri Prashanthi , Kantarci Kejal , Boeve Bradley F. , Whitwell Jennifer L , Josephs Keith A , Petersen Ronald C. , Knopman David S. , Jack Clifford R.
Published: December 2021

Background

Optimizing software to measure Flortaucipir (AV‐1451) tau PET SUVR change‐over‐time is crucial for longitudinal observational studies and potential trials of anti‐tau agents. Ideal measurements should have good repeatability (low noise), and should clearly separate clinical cognitive groups.

Method

We compared 456 software methods varying in their use of: two major packages, each with cross‐sectional and longitudinal variants (FreeSurfer and an in‐house pipeline using SPM12, MCALT, and ANTs); three temporal‐lobe target regions (each with/without adjacent WM); seven reference regions; five PVC methods; and two statistics (mean vs. median). We used linear mixed‐effects models to compare methods using scans from 88 Mayo Clinic participants (46 cognitively impaired, 42 impaired, excluding those with symptoms inconsistent with the AD pathology imaged by Flortaucipir), each with three visits with PET and MRI. From these models, we calculated two criteria for each pipeline: relative measurement error (residual from the linear mixed model), and the t‐statistic for testing differences in group‐wise rates of change (which has a Cohen’s d interpretation of effect size for longitudinal data). We plotted both criteria orthogonally, then ranked methods overall according to the average of their ranks on both individual criteria.

Result

Methods using the entorhinal cortex target region performed poorly in both criteria (Figure 1). The top 10 methods by the combined criteria (top‐left in Figure 2) all used the Mayo SPM12‐based pipeline with an eroded supratentorial WM (eSWM) or composite (eSWM + pons + cerebellum) reference region. Among them, 9/10 used the longitudinal variant, 8/10 used 2‐compartment PVC, and 7/10 used median. Altogether, our results favored SUVR methods with a longitudinal design (simultaneously calculating all time‐points), a temporal‐lobe meta‐ROI including adjacent WM, a composite reference region, 2‐class voxel‐based (Meltzer) PVC, and median statistics. Methods using GTM‐Tau PVC (Baker et al., Data in Brief, 2017) had the highest group separation but relatively large measurement error, giving them ranks 197 and 199 out of 456 with the joint (average rank) criteria.

Conclusion

Compared with popular FreeSurfer‐based methods (ranks 176, 258; Figure 2), our top‐ranked approaches approximately halved error in SUVR measurements while maintaining or improving group separation.
Associations of lifestyle factors with amyloid positivity in cognitively normal individuals at different levels of genetic risk: The amyloid biomarker study
Authors: Oomens Julie Elisabeth , Jansen Willemijn J , Janssen Olin , Verhey Frans RJ , Vos Stephanie JB , Visser Pieter Jelle ,   Amyloid Biomarker Study Group
Published: December 2021

Background

The role of lifestyle factors in the pathophysiology of Alzheimer’s disease is unclear. The aim of this study was to assess the contribution of lifestyle factors to cerebral amyloid pathology in cognitively healthy persons at different levels of genetic risk.

Methods

We selected sixteen cohorts from the Amyloid Biomarker Study. Lifestyle data were available for 5542 participants with normal cognition. Amyloid positivity was determined with amyloid‐PET (center‐specific cutoffs) or with aß42 level in CSF (data‐driven cutoffs). Participants were classified as being at low, intermediate or high genetic risk for amyloid positivity according to ApoE e4 copy number (0 vs. 1 vs. 2 e4‐alleles). Participants for whom data was available for >=3 lifestyle factors (n=5046) were classified as having a favorable or unfavorable lifestyle profile on basis of the lifestyle information available for that cohort. A favorable lifestyle was defined as (dichotomized): not smoking (ever), not drinking, normal sleep, physically active, socially active, cognitively active and/or adhering to a Mediterranean diet. Associations of both lifestyle profile and individual lifestyle factors with amyloid positivity, and their dependency on genetic risk, were assessed using generalized estimating equations. Age was included as covariate in all models,

Results

Independent of genetic risk level, impaired sleep was associated with lower amyloid positivity (p=0.001) and cognitive inactivity was associated with higher amyloid positivity (p<0.001). Smoking, alcohol use, social activity and diet were not associated with amyloid positivity (table 2). The effects of lifestyle profile and physical activity on amyloid positivity were dependent on genetic risk (p<0.001). Prevalence of amyloid positivity was lower for those with a favorable rather than an unfavorable lifestyle at low (mean difference (md) 3%, p<0.001) and intermediate (md 5%, p<0.001) genetic risk, while this association was reversed for persons at high genetic risk (md 7%, p=0.001, table 3). Amyloid positivity was more common in physically active than inactive participants at high genetic risk only (md 9%, p<0.001).

Conclusion

Individual lifestyle factors are limitedly associated with amyloid positivity. However, absence of any unfavorable lifestyle factor is related to lower risk of amyloid positivity in persons at low or intermediate genetic risk.
Sleep disturbance and association with cognitive and functional trajectories in all cause dementia: The Cache County Dementia Progression Study
Authors: Murray Julie , Gonzalez Hector Leonardo , Schwartz Sarah , Rattinger Gail B. , Liu Yin , Hammond Alexandra G , Kauzor Kaitlyn E , Drewel Mikaela , Tschanz JoAnn T
Published: December 2021

Background

Sleep disturbance is common in older adults, with a prevalence rate of approximately 25%. Sleep disturbance has been associated with increased risk for Alzheimer’s disease (AD), brain Aß deposition, and worse cognition in older adults in general. Few studies have examined the association between sleep disturbance and cognitive or functional decline after the onset of dementia. We examined this issue in a population‐based cohort of persons with dementia.

Method

Five hundred eighty‐two participants (aged 65+, 60.3% female) with dementia from the Cache County Memory Study were followed for a mean (sd) of 2.47 (2.72) years, and maximum of 13.28 years. Mean (sd) age of dementia onset was 83.49 (6.29) years. A majority (81.3%) had a high school diploma/GED. Cognition was assessed at baseline and semi‐annual follow‐ups with the Mini‐Mental State Exam (MMSE) and functional status with the Clinical Dementia Rating sum‐of‐boxes (CDR‐sum). Sleep disturbance was based on the sleep domain from the Neuropsychiatric Inventory, or if lacking, a question about the subject being “troubled by sleep problems, insomnia.” Presence of depression was also determined from the NPI. Sleep disturbance (time varying) was examined in separate linear mixed effects models to predict changes in MMSE and CDRsum, controlling for age, gender, education, depression (yes/no) and presence of APOE E4 allele.

Result

Prevalence of sleep disturbance was 29.7%. The association between sleep disturbance and cognitive and functional outcomes varied by dementia type (p interactions < .001). Compared to those with Alzheimer’s disease and sleep disturbance, individuals with vascular dementia and sleep disturbance exhibited worse (higher) CDR‐Sum scores across time (M_difference = ‐1.55, SE = .41, p < .001, d = .27) while individuals with “other dementias” and sleep disturbance performed worse on the MMSE (M_difference = 2.14, SE = .55, p < .001, d = .38) as did APOE4 carriers (M_difference = 1.45, SE = .35, p < .001, d = .26).

Conclusion

Individuals with various dementia types and those with an APOE E4 allele in combination with sleep disturbance had worse cognitive and functional trajectories. Future work will examine effects of sleep medication use on dementia trajectory.
Tau‐PET is associated with knowledge of COVID‐19, COVID‐19‐related distress, and change in sleep quality during the pandemic
Authors: Lussier Firoza Z , Servaes Stijn , Kang Min Su , Bezgin Gleb , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Stevenson Alyssa , Pascoal Tharick A. , King Suzanne , Elgbeili Guillaume , Bzdok Danilo , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2021

Background

While the global COVID‐19 pandemic has hindered many human research operations, it has allowed for the investigation of novel scientific questions. Particularly, the effects of the pandemic and its resulting social isolation on elderly individuals and their association with Alzheimer’s disease biomarkers remains a broad and open question. Here, we sought to investigate whether knowledge of COVID‐19, pandemic‐related distress, and changes in sleep quality were associated with in vivo tau deposition in an AD‐enriched cohort.

Methods

COVID‐19 telephone assessments were conducted in N=292 individuals (29 young/174 CN/52 MCI/19 AD/18 other) of the TRIAD cohort in April‐July 2020. Assessment consisted of clinical and neuropsychiatric, instruments, including scales assessing the individual’s experience of the pandemic. Structural MRI and [18F]MK6240 tau‐PET were acquired before the pandemic. [18F]MK6240 standardized uptake value ratio (SUVR) were calculated 90‐110 minutes post‐injection using cerebellar grey matter as the reference region. Voxel‐based regression analyses were conducted to examine the associations between baseline [18F]MK6240 SUVR and knowledge of COVID‐19, distress related to COVID‐19, and change in sleep quality since the pandemic.

Results

Higher tau‐PET SUVR was associated with less knowledge of COVID‐19 in N=210 individuals in the cuneus, cingulate and superior temporal regions. Tau‐PET was similarly associated with lower levels of COVID‐19‐related distress in the isthmus and rostral anterior cingulate (N=201 individuals). Furthermore, tau‐PET tracer uptake was significantly associated with increases in sleep quality as assessed by rate of change in Pittsburgh Sleep Quality Index before and during the pandemic (N=176 individuals). All results survived correction for multiple comparisons using random field theory with a cluster threshold of p < 0.001.

Conclusion

Our results suggest that those with increased tau deposition may have a weaker understanding of symptoms and prevention of COVID‐19 and lower levels of distress related to the pandemic than individuals with less brain tau. Individuals with higher tau may also experience improved sleep quality during the pandemic. While these observations appear to be favourable effects of tau, the first may suggest that public health information about COVID‐19 is less accessible to the aging population. The interactions and mediation of these effects remain to be properly elucidated.
Care processes related to clinical detection of Alzheimer’s disease in the U.S. Veterans Affairs Health Care System
Authors: Miller Donald R , Jasuja Guneet , Davila Heather W , Palnati Madhuri , Shao Qing , Dinesh Deepika , McDannold Sarah , Zhang Quanwu , Monfared Amir Abbas Tahami , Xia Weiming , Palacios Natalia , Moo Lauren R.
Published: December 2021

Background

Alzheimer’s disease (AD) is a debilitating, progressive brain disorder that diminishes quality of life and represents immense burden of public health. This study characterizes healthcare utilization related to clinical detection of AD and care for AD patients in the US Veterans Affairs (VA) Healthcare System.

Methods

Using the VA Corporate Data Warehouse (2000‐2019), we studied Veterans aged ≥50 years who received ≥2 ICD‐10 codes (G30) for AD, with first code appearing in fiscal year 2018. We identified prior related ICD‐10 codes and summarized care processes during the years before and the year after the first AD code, including referrals to dementia‐related medical specialists (neurologists, geriatricians, geriatric psychiatrists), assessments by neuropsychological tests and radiological brain imaging, dementia medication prescriptions (donepezil, galantamine, memantine, rivastigmine), community‐based services (home health, adult day programs), and placements in institutional long‐term care in VA or community nursing homes.

Results

The study cohort consisted of 6,046 Veterans (mean age of 80 years; 3% women; 22% non‐White race/ethnicity). Prior to the first ICD coding, 53.1% received codes for non‐specific dementia and 29.4% for mild cognitive impairment (MCI), with the first code appearing an average of 3 years before the first AD code. In the year before the first AD code, 51.1% visited specialists, 25.7% received neuropsychological assessments, 31.3% had brain imaging (but only 1.3% had a fluorodeoxyglucose‐PET scan), 30.2% received prescriptions for dementia medication, 45.8% received community‐based services, and 15.0% were admitted to institutional long‐term care. In the year following the initial AD code, 73.2% had specialty visits, 60.5% received dementia prescriptions, 63.6% received community‐based services, and 44.2% were admitted for institutional long‐term care.

Conclusions

Medical and pharmacy utilization for non‐specific dementia or MCI begins years before AD detection, marked by the first AD‐specific clinical encounter in VA. Many AD patients do not receive specialty care and very few undergo a PET scan before AD detection. Community‐based home or day care and institutional nursing care increase with AD detection suggesting a substantial need for healthcare resources.
Increased CRP and triglyceride level associate with accelerated progression of Alzheimer's disease
Authors: Horvath Andras Attila
Published: December 2021

Background

Alzheimer patients show various progression, so therapeutic considerations may also vary from individual to individual. Cardiovascular risk factors were analyzed in a prospective follow‐up.

Method

We included 112 Alzheimer’s patients for follow‐up. We collected epidemiological, demographic, and clinical data. Structural MRI, neuropsychological, and complete laboratory examinations including cardiovascular risk factors (CRP, cholesterol, triglyceride) were performed. Progression was monitored by repeated neuropsychological examinations for 3 years. Correlation analysis between laboratory, neuropsychological and structural MR values obtained at the time of diagnosis and group comparison for cardiovascular risks were used in the 0‐time point study. In the prospective study, correlation analysis and ANCOVA analysis were performed between the rate of cognitive impairment and laboratory values.

Result

The age of the studied patients was 74.3 ± 4.6 at the onset of the disease. No correlation was found between the examined values in the analysis at 0‐time point (all p> 0.05). However, in the prospective study, we found positive correlation between baseline triglyceride levels and disease worsening (r = + 0.27; p = 0.011). We also found significant correlation between baseline CRP levels and disease deterioration (r = + 0.53; p = 0.009), which was also confirmed by ANCOVA analysis taking into account age, sex, disease onset, and disease severity as covariance. There was a significant difference between the + 2SD and ‐2SD groups calculated for the mean CRP mean (F = 44.61, p = 0.013).

Conclusion

At the time of diagnosis, there is no direct correlation between laboratory values and disease status, however, initial triglyceride and CRP values may indicate subsequent disease progression. Higher triglyceride and CRP levels are associated with increased disease progression, so these assays may be suitable for risk stratification and modification may be a therapeutic option to be considered individually.
Non‐invasive AI model for human functional patterns recognition in IADLs
Authors: Acosta‐Franco Jesus Alejandro , García‐Moreno Ciro Andrés Martínez , García‐Vázquez Mireya Saraí , Ramírez‐Acosta Alejandro Álvaro
Published: December 2021

Background

Alzheimer's Disease (AD) diagnosis at early stages currently represents an important challenge for the scientific community, which is gradually accentuated due to the global perspective of population aging. Current clinical processes for the diagnosis of this disease are increasingly effective; these include invasive tests of nervous system biomarkers, which are complemented by non‐invasive tests of human cognitive and functional performance, such as the mini‐mental state examination and the analysis of Instrumental Activities of Daily Living (IADLs).

Method

The present work is centered around the development of technological tools for creating an automated model to support the diagnosis of early AD disease. We present a novel non‐invasive methodology for the development of an Artificial Intelligence‐based model, which analyzes human biomechanical markers of IADLs activities to recognize human functional patterns. For the development of this model, we have built a dataset of egocentric videos containing IADLs activities, organized in four classes, based on the prehensile patterns of the hands: strength and precision, and on the kinematics of the instruments: displacement and manipulation. We have characterized the dataset using mathematical methods to get information to directly emulate the relationship with Lawton and Brody's geriatric test, which is used in clinical protocols to estimate human functional capacity. This characterization relationship between biomechanical markers and human functional patterns represents a benefit for quantitative and objective assessment in support of geriatric evaluation and patient follow‐up.

Result

Our proposed model results in an accuracy of 73.74% in the recognition of human functional patterns related to the kinematics of the instruments, 59.84% in the analysis of the prehensile pattern of the hands, and 48.5% when the classes were recognized independently.

Conclusion

This allows us to establish in a quantifiable way performance region benchmarks of human functional capacity for IADLs activities, by obtaining a support model in the diagnostic evaluation of AD disease at early stages. Our proposed model allows us to establish the guideline to improve the automatic recognition of human functional patterns, of which we obtained an acceptable percentage testing instruments kinematics', followed by the hands' prehensile patterns.
17alpha‐estradiol improves systemic and neural outcomes in middle‐aged APOE4 mice
Authors: Qian Wenjie , Christensen Amy , Lu Ryan , Finch Caleb E , Benayoun Bérénice A. , Pike Christian J.
Published: December 2021

Background

In this study, we investigate the hypothesis that recently identified longevity‐promoting intervention 17α‐estradiol (17αE2) will protect against senescent changes in brain and throughout the body that are associated with APOE4 and heightened AD risk. The most significant genetic factor for late‐onset Alzheimer’s disease (AD) is the apolipoprotein E gene (APOE): AD risk is reduced by the APOE2 variant and increased by the APOE4 variant. APOE genotype is associated with longevity in the same pattern, with APOE2 linked with increased and APOE4 with decreased lifespan. This is of particular interest as advanced age is the single greatest risk factor for AD. Indeed, APOE genotype may regulate AD vulnerability in part by affecting aging processes. Thus, compounds that increase health and longevity may be particularly relevant to APOE4‐associated AD risk.

Method

Male mice homozygous for human APOE3 or APOE4 were maintained on normal chow in the absence or presence of 14.4 ppm 17αE2 for 20 weeks, starting at age 10 months. Animals were assessed on a range of systemic metabolic, inflammatory, and frailty outcomes as well as on established areas of APOE4‐associated neural impairment, including neuroinflammation, neurogenesis, and cognition.

Result

In middle‐aged male mice, APOE4 genotype was associated with significantly poorer systemic and neural phenotypes relative to APOE3 genotype. In general, treatment with 17αE2 yielded improvements in both APOE3 and APOE4 mice across multiple measures, though the benefits were typically much stronger in APOE4 mice. For example, 17αE2 reduced body weight, plasma leptin, hepatic steatosis, and frailty index more strongly in APOE4 than APOE3 mice. Neural results are pending.

Conclusion

These data confirm and extend prior findings that APOE4 is associated with senescent effects both peripherally and neurally, outcomes linked with AD risk. Importantly, 17αE2 significantly improved a range of measures. This study will establish proof‐of‐principle for 17αE2 as an AD therapeutic with efficacy predicted to be strongest in APOE4 genotype. Given that the majority of AD cases in the U.S. are APOE4 carriers, mitigating the effects of APOE4 would have significant therapeutic potential.

Supported by the NIA (RF1AG058068) and the Cure Alzheimer’s Fund.
Aetiology and prognosis of the motoric cognitive risk syndrome: A population‐based comparison with mild cognitive impairment
Authors: Yaqub Amber , Darweesh Sirwan K.L. , Dommershuijsen Lisanne J. , Wolters Frank J. , Ikram M. Arfan
Published: December 2021

Background

The motoric cognitive risk syndrome (MCRS) has been proposed as a dementia prodrome that improves clinical risk stratification, by integrating slow gait and cognitive complaints. It remains undetermined to what extent pathophysiological substrates in terms of clinical risk factors, neuroimaging correlates and associations of MCRS with dementia are independent of the widely used concept of mild cognitive impairment (MCI).

Methods

Between 2009 and 2015, subjective cognitive complaints, objective cognitive impairment and gait speed were assessed in 3,025 dementia‐free participants of the population‐based Rotterdam Study (mean age 70.4 years, 54.7% women). In line with prior studies, MCI and MCRS were defined as subjective complaints along with a score of >1.5 and >1 standard deviations below the population mean of the neuropsychological test battery and gait speed, respectively. We used multinomial logistic regression models to determine cross‐sectional associations of clinical risk factors and neuroimaging markers with MCI and MCRS, and subsequently assessed risk of dementia or death, with follow‐up until 2016, in a competing risk framework.

Results

Of 3,025 individuals, 231 had MCRS (7.6%), 132 had MCI (4.4%), and 62 (2.0%) fulfilled criteria for both. Smoking, hypertension, diabetes and APOE‐ε4 carriership were shared risk factors between MCRS and MCI, but higher BMI predisposed predominantly to MCRS, whereas male sex and hypercholesterolemia were associated with MCI only. Lower total brain volume was more strongly related to MCI than to MCRS, driven by a difference in white matter volume. During a mean follow‐up of 3.9 years, 71 individuals developed dementia and 200 died. Compared to unaffected individuals, risk of dementia was higher with MCI and to a lesser extent with MRCS (subdistribution hazard ratio [95% confidence interval]: 6.95 [3.78‐12.75] and 3.55 [1.91‐6.60], respectively). Accounting for a higher mortality risk, 5‐year risk of dementia was 7.0% [2.5‐11.5%] for individuals with MCRS, versus 13.3% [5.8‐20.8%] with MCI and 2.3% [1.5‐3.1%] in unaffected individuals.

Conclusion

In people with subjective cognitive complaints, both cognitive and motor function impairment are associated with dementia risk, with in part different pathophysiological substrates. While MCI has greater utility for dementia prediction, incorporation of motor function in clinical assessments may increase prognostic accuracy.
Healthy lifestyle and cognitive decline in people living with stroke in the community
Authors: Dhana Klodian , Aggarwal Neelum T , Beck Todd , Desai Pankaja , Liu Xiaoran , Barnes Lisa L , Evans Denis A , Rajan Kumar B
Published: December 2021

Background

A healthy lifestyle is associated with a slower cognitive decline and reduced risk of Alzheimer’s dementia in the general population. Whether such a healthy lifestyle exerts cognitive benefits among people living with stroke in the community deserves examination.

Method

The analyses used 5,324 older individuals without dementia participating in the Chicago Health and Aging Project, a population‐based cohort study. Of 5,324 participants, 1,030 individuals had a stroke at the baseline or developed it over study period. We followed up 1,030 participants with stroke and 1,030 stroke‐free individuals matched by age, sex, race, and examination cycle, for changes in cognitive functioning. The primary exposure was healthy lifestyle score that included five factors, non‐smoking, moderate exercise, being cognitively active, having a high‐quality diet, and limiting alcohol use – giving an overall score ranging from 0 to 5. Global cognitive function was evaluated every 3‐years using a short‐battery tests consisting of two tests of episodic memory, one test of executive function, and the MMSE. Multivariable adjusted linear mixed effect models were used to estimate the role of a healthy lifestyle score on cognitive decline.

Result

The average age of participants with stroke was 76 years, 62% were women, and 64% were African Americans. These characteristics were similar to the overall study population (n=5,324). Compared to people without stroke, participants with stroke had 22.3% (beta ‐0.019 unit/year; 95%CI ‐0.03, ‐0.008) faster cognitive decline during follow‐up. The healthy lifestyle score was associated with a slower cognitive decline in participants with and without stroke. Each unit increase in healthy lifestyle was associated with 8.7% (beta 0.010 unit/year; 95% 0.001, 0.018) slower annual cognitive decline in people with stroke and 7.3% in people without stroke. The annual cognitive decline rate in individuals with 4‐5 healthy lifestyle factors compared with those with 0‐1 factor was 32.7% (beta 0.033 unit/year; 95%CI 0.002, 0.064) slower in participants with stroke and 34.0% (beta 0.030 unit/year; 95%CI 0.006, 0.053) slower in participants without stroke.

Conclusion

In community‐dwelling stroke survivors, a higher healthy lifestyle score was associated with better cognitive functioning, suggesting that these lifestyle factors may exert cognitive benefits after stroke.
The influence of cognitive ability on older adults’ ability to take over driving control from an automated vehicle
Authors: Haghzare Shabnam , Campos Jennifer L. , Delfi Ghazaleh , Stasiulis Elaine , Rapoport Mark , Naglie Gary , Mihailidis Alex
Published: December 2021

Background

Automated vehicles (AVs) hold potential promise in sustaining the safe mobility of older adults whose driving is compromised due to cognitive impairments. However, current AVs have an operational limit and when this limit is reached, the driver is expected to promptly take over driving control. The timely performance of takeover task draws upon cognitive resources that can be compromised in people with dementia (PwD) and people with Mild Cognitive Impairments (PwMCI). Therefore, this study investigates the abilities of PwD and PwMCI to perform an AV driving takeover task.

Method

Population. 20 participants per three groups of PwD, PwMCI, and older adult controls will be recruited. Currently, the data collection for the controls and recruitment for the PwD and PwMCI are on‐going. The present results are based on seven control participants who have completed the study to date. Study Design & Setting. Participants completed a battery of sensory and cognitive tests and performed takeover tasks in response to an audio‐visual alert in a simulated AV using a high‐fidelity driving simulator. Each participant performed takeovers in eight driving conditions varying in lighting level (day/night), road structure (straight/curved), and speed limit (60/120 km/h). Measures. To characterize participants’ takeover abilities, their response time was measured as the time interval between the audio‐visual alert and uptakes in speed (longitudinal takeover time), and changes in steering wheel angle (lateral takeover time).

Result

A correlation analysis was conducted between each of takeover time measures and cognitive and visual tests. MoCA scores showed a significant, negative correlation with lateral takeover time (r
k = ‐0.85, p = .015, 95% CI [‐0.98, ‐0.27]). To investigate the effects of driving condition on takeover time, pairwise Kruskal‐Wallis tests were conducted on measures of takeover time as separated by driving condition. Significant differences were only observed in lateral takeover time in the curved, high‐speed condition compared to other conditions (χ2(3) = 29.46, p < .001).

Conclusion

This study will help clarify the associations between older adults’ cognitive abilities and takeover abilities in AVs which can, in turn, inform the guidelines around the safe use of AVs by PwD and PwMCI.
Predictive factors for conversion to dementia in individuals with early‐onset mild cognitive impairment
Authors: Baird Kate , Baillon Sarah , Lau Lilian , Storey Mathew , Lindesay James , Velayudhan Latha
Published: December 2021

Background

Early‐onset Mild Cognitive Impairment (eoMCI) is defined as difficulties in cognition that are worse than in normal ageing for individuals below the age of 65. Some will go on to develop dementia, but there is currently limited research on which risk factors make someone more vulnerable to conversion. The present study aimed to examine whether sociodemographic and clinical factors at the initial presentation predict dementia progression in a cohort of eoMCI patients attending a memory service, at a university teaching hospital in the United Kingdom.

Methods

A retrospective case note study utilising a database of individuals diagnosed with eoMCI between 2000‐2010 at a Younger Person’s Memory Service (YPMS) in Leicestershire, England. Data collected at assessment included social factors, demographic characteristics, medical and psychiatric history, as well as standardised cognitive assessment scores.

Results

Out of 531 subjects who attended YPMS between Jan 2000 to Dec 2010, 65 patients were diagnosed with eoMCI (47.7% female; age 56.4 years ±7.54). Of these, 21 individuals (32.3.%) converted to dementia during their course within the service. The mean period of conversion was 30.40 months (±23.08). A comparison between the subgroups revealed a significant association between dementia conversion and higher years of education, lower MMSE and CAMCOG (total and subscores) scores. A subsequent survival analysis found that higher education, lower CAMCOG score, impaired memory (remote, recent, learning) and impaired executive functions, at initial assessment were significant predictors for converting to dementia.

Conclusion

Higher education, impaired memory and impaired executive functions at initial assessment are associated with a progression to a dementia diagnosis. The present naturalistic study identifies potential characteristics that predict the likelihood of an individual with eoMCI converting to any type of dementia. This has vital clinical implications and additional research is needed to explore these risk factors further.
Acute cerebral blood flow response to lipid ingestion in older adults: A pilot study
Authors: Ashford Nathaniel K. , Rane Swati , Gandhi Tarun , Farris Kristen , Hanson Angela J.
Published: December 2021

Background

High fat feeding (HFF) is a risk factor for Alzheimer’s disease (AD), and acute meal studies including lipid tolerance tests can be used to understand mechanisms by which diet affects disease processes. This study seeks to describe cerebral blood flow (CBF) response using arterial spin labeling (ASL) MRI, given the tight coupling of CBF to brain metabolism.

Method

After fasting, 16 older adults (age 66.3±2.9) underwent baseline and 1, 2, 3‐hour ASL MRI after ingestion of 1/2 cup heavy cream with comparable total and saturated fat to a high fat breakfast. We used pCASL MRI with background suppression to measure CBF in ml/100g/min. Imaging parameters were in accordance with the recommendations of ISMRM: label duration = 1.8 s, post‐labeling delay = 2 s, labeling offset = 25‐30 mm, slices = 20, resolution = 3.5×3.5×5 mm3, SENSE‐factor = 2, TR/TE= 5000/18 ms. Finally, we acquired a reference scan (M0, 1 minute) identical to the above scan but with TR = 10,000 ms and no labeling or background suppression. Statistical analyses included paired t tests and ANOVA for group comparisons.

Result

Global CBF decreased at 1, 2, and 3 hours post‐lipid drink, compared to time 0 (1h:‐2.12±4.1, 2h:‐1.9±3.2, 3h:‐2.9±3.1); only 2 and 3 hours were statistically lower. No group differences by sex or APOE status were noted in baseline or change CBF for this small pilot sample.

Conclusion

Global CBF decreased after lipid ingestion, similar to what has been reported with glucose and fructose ingestion. Sustained decreases in CBF were still detectable at 3 hours. Future studies include investigation of pre‐post CBF in various regions known to be affected by AD.
Spatiotemporal trends in dementia‐associated deaths, what do the data reveal?
Authors: Parkinson Luisa , Lindgren Finn , Russ Tom C
Published: December 2021

Background

Data on dementia mortality are routinely collected by governments and used in health research. However, historical underrecording of dementia on death certificates has limited the utility of this widely available data source. Considerable effort has been invested in raising awareness of dementia, increasing diagnosis rates, and improving dementia recording on death certificates. Updated versions of the ICD‐10 rules for coding the underlying cause of death, implemented in Scotland in 2011 and 2017, have increasingly assigned deaths that mention both dementia and respiratory or urinary tract infections towards an underlying cause of dementia, if no other underlying medical condition is mentioned. Since previous cohort studies have shown geographical variation in dementia risk, this study utilises spatiotemporal modelling to investigate changes in dementia‐associated deaths in Scotland.

Method

Data on dementia and Alzheimer’s deaths and mid‐year population estimates available from the National Records of Scotland for the time period 2000‐2019 were used to build a Bayesian spatiotemporal disease mapping model. The data were grouped by the 32 Council areas and year, whilst stratification by age and gender were built into the model. The analyses were run in R using Integrated Nested Laplace Approximation methodology.

Result

The data show strong temporal and spatial trends in the relative risk of dementia‐associated death. The relative risk increases progressively over the time period studied, with a 2.3‐fold increase (95% Confidence Interval: 2.1‐2.5) between 2000 and 2019, reaching levels just below predicted dementia prevalence in recent years. The relative risk varies geographically and is highest in Scotland’s industrialised central belt region and lowest in the rural areas and islands, with a relative risk of 1.9 (95% CI: 1.6‐2.3) between the lowest and highest risk Council areas.

Conclusion

There are factors, other than the step changes in underlying cause of death coding, driving the progressively increasing temporal trend in relative risk of dementia‐associated death. These factors could be a combination of increased dementia awareness, a larger proportion of people being diagnosed, greater recording on death certificates and, possibly, increasing prevalence. The strong spatial variation in relative risk in Scotland indicates that there are geographically‐varying factors affecting this risk.
Apathy across neurodegenerative disorders is associated with sex‐specific changes in sub‐cortical and cortical grey matter volumes
Authors: Tumati Shankar , Lanctôt Krista L. , Seitz Dallas , Herrmann Nathan
Published: December 2021

Background

Apathy is frequent in all neurodegenerative disorders (ND) but it is not known whether apathy across these diagnostic groups is associated with common brain changes. Here, we investigated if MRI‐derived grey matter volumes (GMV) predicted apathy across these disorders.

Method

Subjects from the Canadian Consortium on Neurodegeneration in Aging’s COMPASS‐ND cohort were diagnosed with clinical and MRI assessments. Apathy was defined on the Neuropsychiatric Inventory questionnaire. GMV derived from cortical and sub‐cortical regions were used to predict apathy in subjects with ND, controlling for age, sex, years of education (YoE), and total GMV.

Result

Included subjects (n=386, 72.5 ± 7.3y, 43.5% F, YoE: 15.6 ± 3.8y, Montreal Cognitive Assessment score (MoCA): 23 ± 4.4) were diagnosed with subjective cognitive impairment (n=55), mild cognitive impairment (MCI, n=144), Alzheimer’s disease (n=56), Parkinson’s disease (PD) without cognitive impairment (n=34), PD‐MCI (n=23), PD dementia (n=6), vascular MCI (n=15), mixed dementia (n=25), Lewy body dementia (n=14), and Frontotemporal dementia (n=12).

Apathy was present in 114 (29.5%, 72.9 ± 7.2y, 23.7% F, YoE: 15.3 ± 4.1y, MoCA: 21.1 ± 4.2) subjects. After adjusting for covariates, apathy was predicted by lower left (B=‐2.37, z=‐2.84, pfdr=.044) and higher right GMV (B=2.34, z=2.92, pfdr=.044) of the caudate nucleus. Apathy was better predicted by men (B=1.36, z=3.89, pfdr=.003); hence the analysis was repeated separately in men and women. In men (n=218, apathy=87), in addition to caudate GMV (left: B=‐2.79, z=‐2.73, pfdr=.044; right: B=2.85, z=2.83, pfdr=.044), apathy was predicted by higher left (B=2.74, z=2.84, pfdr =.044) and lower right (B=‐3.42, z=‐3.32, pfdr=.025) GMV in the putamen; in women (n=168, apathy= 27), apathy was predicted by higher left (B=22.4, z=3.5, pfdr =.006) and lower right (B=‐21.85, z= ‐3.64, pfdr =.006) frontal lobe GMV but not caudate GMV.

Conclusion

In a large cohort of ND patients, GMV changes in caudate nuclei were associated with apathy. Importantly, apathy in women was associated with frontal lobe GMV changes, suggesting that the neural correlates of apathy might differ in men and women.
Co‐designing toolkits to improve post‐diagnostic support for people living with dementia, care partners and health and social care professionals (COGNISANCE)
Authors: Wilcock Jane , Poole Marie , Brodaty Henry , Robinson Louise , Rait Greta ,   Cognisance Research Team
Published: December 2021

Background

COGNISANCE is an international research programme (Australia, UK, Canada, Netherlands, and Poland). In partnership with people living with dementia, informal care partners, health and social care professionals and key national and international dementia organisations and researchers, we have co‐designed online toolkits aiming to improve post‐diagnostic support for dementia.

Methods

We have worked closely with local working groups representing members from key audiences and a design and marketing agency to run a series of workshops in five countries. The workshops to date have focussed on the key messages, motivators for information seeking, experiences of dementia diagnosis and post diagnostic support, the purpose for toolkits and the tone and branding appropriate for the key audiences for a resource that focusses on the first twelve months post‐diagnosis.

Results

Co‐design workshops were successfully run concurrently in five partner countries. Each country’s research team and local working groups remained highly engaged throughout the process. Key motivators for the toolkits led to a focus on a practical and empathetic resource that was tailored to the individual. The toolkits will be a website that has three separate pathways, one for people recently diagnosed with dementia, one for care partners and one for health and social care professionals. These will function to support communicating the diagnosis, post‐diagnostic support and planning for the first year post diagnosis. The design and marketing agency have worked closely with research teams and local working groups throughout the co‐design process to interpret and build iteratively on each workshop outcome. From this we have successfully produced a generic website that can be tailored in different locations to the three key audiences.

Conclusion

In the co‐design process, representative users identified the need for a practical, empathetic and individually‐tailored resource. The toolkit will be a website that has an individual planning tool for the first twelve months following a dementia diagnosis. We are continuing the co‐design process to develop a campaign. This will promote the key messages and toolkit, to plan for a life with dementia, ahead of user testing, implementation and evaluation.