bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex differences in the behavioral variant of frontotemporal dementia: A new window to executive and behavioral reserve
Authors: Illán‐Gala Ignacio , Casaletto Kaitlin B. , Borrego‐Écija Sergi , Arenaza‐Urquijo Eider M , Wolf Amy , Cobigo Yann , Goh Sheng‐Yang Matthew , Staffaroni Adam M. , Alcolea Daniel , Fortea Juan , Blesa Rafael , Clarimon Jordi , Iulita M. Florencia , Brugulat‐Serrat Anna , Lladó Albert , Grinberg Lea T. , Possin Kate L , Rankin Katherine P , Kramer Joel H , Rabinovici Gil D. , Boxer Adam L. , Seeley William W. , Sturm Virginia , Tempini Maria Luisa Gorno , Miller Bruce L. , Sanchez‐Valle Raquel , Perry David C. , Lleó Alberto , Rosen Howard J.
Published: December 2021

Background

The behavioral variant of frontotemporal dementia (bvFTD) is characterized by progressive behavioral change along with social, cognitive, and functional deterioration. In contrast Alzheimer´s disease, patients with bvFTD show an anterior pattern of neurodegeneration with selective involvement of the frontotemporal cortex. Biological sex is an increasingly recognized factor driving clinical heterogeneity in Alzheimer's disease, but its role in bvFTD is unknown.

Method

In this multicenter study, we aimed to characterize the impact of sex on clinical presentation, longitudinal decline, and cortical thickness in bvFTD. We included 216 patients with bvFTD and 235 controls with MRI. We compared the clinical characteristics and cortical thickness between men and women with bvFTD and controls. We further explored the existence of sex differences in cognitive reserve by following the residuals approach to operationalize reserve as having better cognition and fewer behavioral changes than predicted by cortical thickness (a proxy of pathology). To do this, we modeled the relationship between cognition or behavior with cortical thickness and used each individual's residual as a proxy of their reserve.

Result

At diagnosis, women with bvFTD showed greater atrophy burden in frontotemporal regions compared to men despite very subtle differences in cognitive and functional impairment, progression, and survival. For a similar amount of atrophy, women demonstrated better‐than‐expected scores on executive function and less apathy, sleep, and appetite changes than men.

Conclusion

Our findings suggest that women might have greater behavioral and executive reserve than men. Future studies should examine the specific mechanisms underlying the observed differences and consider biological sex for the design of research studies and clinical trials in bvFTD and other frontotemporal lobar degeneration syndromes.
Blood and digital markers: Novel findings and its implication on dementia care in China
Authors: Jia Jianping , Jia Longfei , Li Tingting , Yang Jianwei , Song Yang
Published: December 2021

Background

As an aging country with a large population, China has the largest population of patients with dementia in the world (10‐11million patients aged 60 years or older), accounting for approximately 25% of the entire population with dementia worldwide. Currently in China, due to the differences between tier 1, 2, and 3 hospitals (Fig 1), only at academic hospitals affiliated to medical university, the diagnosis of dementia is determined to standard procedures, while more patients with cognitive impairment are diagnosed by neurologists or internists without specialized training in dementia. Exosomes are an attractive source of biomarkers in AD, with its accessibility, generalizability and availability advantages over CSF or PET gold standard.

Method

We will present two of our latest findings based on two multicenter studies and explore the impact of novel blood and digital markers on dementia care in China.

Result

Our latest findings indicated that exosomal biomarkers ‐ in particular, Aβ42, T‐tau, P‐T181‐tau, growth associated protein 43 (GAP43), neurogranin, synaptosome associated protein 25 (SNAP25), and synaptotagmin 1 ‐ had the same diagnostic power as the CSF biomarkers. Moreover, the combination of exosomal GAP43, neurogranin, SNAP25, and synaptotagmin 1 detected AD 5 to 7 years before cognitive impairment.

Conclusion

According to our latest results, exosomal biomarkers could predict AD at asymptomatic stage, making an effective intervention to slow or halt the progression of AD possible. Provided that diagnosis of dementia depends on validated plasma biomarkers, AD would be easily diagnosed in tier 1 or tier 2 hospitals in China. Then, tier1 or tier 2 hospital will play more important role in AD diagnosis, monitoring and patients’ enrolment in clinical trials. Tier 3 hospitals will focus on the diagnosis and treatment of difficult and complicated cases transferred from tier 1 or tier 2 hospitals as well as treatment decision. They will have more time and resources for exploring new mechanism, interventions, translational research and clinical trials.
Automated speech analysis for detection of cognitive and emotional changes
Authors: König Alexandra , Ramakers Inez H.G.B. , Linz Nicklas , Zeghari Radia , Robert Philippe
Published: December 2021

Background

Many aspects of language and speech seem affected with increased dementia risk. Recently speech analysis has become mature enough to provide completely automatically extracted fine‐grained features highly sensitive to early cognitive and affective changes.

Method

Several studies were performed during which over 150 speech samples of patients at different stages (controls, Mild Cognitive Impairment, Dementia) were collected at the clinic as well as remotely (over the phone and video‐conference system). Subsamples of patients with apathy and depression were included. The spoken features extracted from the recordings were compared against data from classical assessment tools and manual annotations.

Result

Comparison to reference measures show firstly, highly accuracies in demonstrating speech differences based on clinical diagnosis (up to 90%) and secondly, significant correlations between automatically extracted and manually annotated measures (r = 0.9).

Conclusion

Speech and language features represent a promising biomarker candidate as they can be automatically and remotely extracted even over the telephone. With the help of advanced machine learning and different computational techniques the most significant markers can be identified as early indicator for screening.
Socioeconomic inequalities in dementia diagnostic process and medication prescription: Experience from the Swedish Dementia Registry
Authors: Hoang Minh Tuan , Kåreholt Ingemar , von Koch Lena , Xu Hong , Secnik Juraj , Religa Dorota , Tan Edwin CK , Johnell Kristina , Garcia‐Ptacek Sara
Published: December 2021

Background

Lower socioeconomic position (SEP) was associated with higher risk of morbidity and mortality. However, the influence of SEP on diagnosis and medication use in dementia is understudied. Our study aimed to explore the impact of patients’ SEP on dementia diagnostic process and medications.

Method

In this longitudinal cohort study, data from 74,414 dementia patients registered in the Swedish Dementia Registry (2007‐2018) were linked with the Swedish Longitudinal Integrated Database for Health Insurance and Labor Market Studies (2006‐2017). SEP was expressed through education and disposable individual income. Outcomes included performance of the dementia diagnostic examinations and prescription of anti‐dementia drugs. The complete basic diagnostic work‐up comprising blood testing, neuroimaging, clock‐test and Mini‐Mental State Examination (MMSE) was suggested by the diagnostic guidelines for dementia from the Swedish National Board of Health and Welfare and was the main study outcome.

Result

In comparison with patients who completed compulsory education < 9 years, patients with university ≥3 years had higher probability of receiving the basic diagnostic work‐up (odds ratio (OR) 1.19; 95% confidence interval (CI) 1.10‐1.29), clock test (OR 1.12; 95%CI 1.02‐1.24) and CT‐MRI (OR 1.23; 95%CI 1.09‐1.39). Compared with people in the lowest income quintile, patients in the highest income quintile presented higher chance of receiving the basic diagnostic work‐up (OR 1.35; 95%CI 1.26‐1.46), clock test (OR 1.40; 95%CI 1.28‐1.52), blood analysis (OR 1.21; 95%CI 1.06‐1.39), MMSE (OR 1.47; 95%CI 1.26‐1.70) and CT‐MRI (OR 1.30; 95%CI 1.18‐1.44). Higher SEP was significantly associated with higher chance of being diagnosed at a specialist care. People with higher income were more likely to receive a specific dementia diagnosis, as opposed to “unspecified” dementia. SEP presented no association with prescription of anti‐dementia medication, except for the association between education and the use of memantine.

Conclusion

Inequalities in dementia diagnostic process and prescription of anti‐dementia medications occur among people with different education or income levels. Income was more decisive than education in the relation to dementia diagnostic process.
Prodromal markers of neurodegenerative disease: Insights from the UK Biobank dataset
Authors: Street Duncan , Whiteside David , Rittman Timothy , Rowe James B.
Published: December 2021

Background

Abnormal quantitative motor testing and subtle cognitive deficits are associated with increased neurodegenerative disease risk although assessment methods and outcomes vary. Understanding how and when these deficits develop will improve early detection and clarify prodromal disease course. We set out to determine markers predictive of two common neurodegenerative diseases, Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), in a prospective cohort study.

Method

The UK Biobank dataset includes demographics, medical history, cognitive function tests and physical measures collected from 500,000 adults aged 40‐69 between 2006‐2010. Ongoing follow‐up includes repeat testing, death registry and hospital diagnostic coding. Cases were identified from hospital coding data and death registry and were matched with age and gender‐similar controls (2:1). Those with a known diagnosis at baseline were excluded.

Result

2248 AD cases (male=48%, mean age 65.3±4.2 years, mean time to diagnosis 8.4±2.5 years) and 2212 PD cases (male=62%, mean age 63.8±5.2 years, mean time to diagnosis 7.7±2.7 years) were identified. 537/2248 (male=51%) AD cases had died by June 2020 (mean assessment to death 9.8±2.0 years) and 357/2212 (male=70%) PD cases (mean assessment to death 9.4±2.2 years). The AD group had shown poorer performance on tasks of fluid intelligence (p<0.0001) and numeric memory (p<0.0001) at baseline than both controls and the PD group. Both AD and PD groups had had slower reaction times (p<0.0001) and weaker hand grip strength at baseline (p<0.0001) than controls. There were no significant effects of age or sex.

Conclusion

Poor performance on tasks of cognitive function are established features of AD at diagnosis, however it is unknown when during the prodromal disease course they begin. Our data demonstrate subtle changes in markers of these features many years prior to diagnosis in a large, prospective cohort.
Domain‐specific cognitive trajectory among patients with minor stroke or transient ischemic attack in a 6‐year Asian cohort: Temporal patterns and indicators
Authors: Zhao Xuhao
Published: December 2021

Background

This study aimed to assess the 6‐year domain‐specific patterns of cognitive trajectory among survivors of minor stroke or transient ischemic attack (TIA) in a multi‐ethnic clinical cohort in Singapore, and to identify possible demographic, clinical and vascular indicators of different trajectory patterns.

Method

Elderly participants completed cognitive and clinical assessments at 2 weeks, 3‐6 months, 1 year, 3/4 years, 5 years and 6 years post‐stroke. Global and domain‐specific cognition was transformed to standardized z‐scores. Generalized estimating equation and mixed linear model were used to examine baseline predictors of long‐term cognitive impairment and domain‐specific cognitive trajectory. Survival analysis was performed for incident cognitive impairment during the 6‐year study duration.

Result

A total of 244 participants were included in the analysis. A fluctuating yet stable pattern was observed in all cognitive domains, except for visual memory, which showed a significant improvement across the six‐year follow‐up. Regardless of baseline characteristics, baseline MoCA was associated with lower odds of long‐term cognitive impairment (0.67, 95%CI= (0.60, 0.75)), whilst both MoCA improvement from baseline to 3‐6 months, and from baseline to 1 year were associated with lower risk of cognitive impairment (OR 0.80, 95%CI= (0.71, 0.90) and 0.86, 95%CI= (0.77, 0.97) respectively) after controlling for covariates.

Conclusion

Post‐stroke cognitive trajectory showed varying patterns across different cognitive domains. Our findings provide evidence on practice effects of the MoCA which can be used for identifying patients with higher risk of long‐term cognitive impairment.
Evidence of significant cognitive improvement over baseline in advanced Alzheimer’s disease (AD) patients: A regenerative therapeutic strategy
Authors: Alkon Daniel , Sun Miao‐Kun , Thompson Richard
Published: December 2021

Background

Synaptogenix scientists have pioneered a regenerative therapeutic strategy designed to reduce (1.) a beta‐oligomers and hyperphosphorylated tau, but importantly, (2.) also restores the AD – induced loss of synaptic networks and neurons. In pre‐clinical studies (Sun and Alkon, TIPS, 2019), increased numbers of mature, mushroom spine synapses were measured with serial electron micrographs of the hippocampus with the rat spatial maze memory task, and were further significantly increased by the Bryostatin‐induced activation of the PKC epsilon‐BDNF cascade (Hongpaisan and Alkon, PNAS, 2007). Similarly, Bryostatin increased the numbers of mature synapses, normalized cognitive deficits, and prevented neuronal death in pre‐clinical models of neurodegeneration including AD (p<.01, 2‐tailed), stroke, Fragile X syndrome, and traumatic brain injury. Subsequently, compassionate use trials showed marked improvements in advanced AD patients (Nelson et al., JAD, 2017).

Method

Thereafter, an initial pilot (13 weeks, N=150) trial of Bryostatin to treat AD, Study #202, and a 2nd (13 weeks, N=100) pilot trial, Study #203, included identical protocols: 7 i.v. doses of 20 mcg / kg Bryostatin over 11 weeks with Placebo groups in each.

Results

Bryostatin Treatment (at Week #13) in the 1st trial improved Severe Impairment Battery (SIB) scores over baseline (+4.5 over baseline, p<.04, 2‐tailed, pre‐specified exploratory analyses of AD patients, MMSE 14 – 4, vs. placebo, without chronic Namenda, Farlow et al., J. Alz. Dis., 2019). In a second pilot trial, Bryostatin caused significant SIB improvement (+4.12 over baseline) in the pre‐specified Moderate Stratum (MMSE 10 – 14) of advanced AD patients without Namenda (p < .005, 2‐tailed). In both trials, trend analyses demonstrated increased drug benefit with increasing dosing number. In a pooled trend analysis of Studies #202, 203, Bryostatin caused highly significant benefit (p<.001) and Placebo was NS.

Conclusion

While issues such as baseline imbalance (Study #203) and Namenda blockade of Bryostatin efficacy (Study #202) prevented reaching primary endpoints, these pre‐specified exploratory analyses (see above) revealed clear evidence of Bryostatin therapeutic efficacy, now being tested in an NIH‐sponsored, 6‐month trial, incorporating lessons learned from these pilot studies. This potential efficacy involved significant improvement over baseline, not only reduction in the rate of cognitive decline.
Towards a fully automatic AI framework to calculate voxel‐wise atrophy in the human brain
Authors: Reinwald Michael , Joules Richard , Papoutsi Marina , Weatheritt Jack , Wolz Robin
Published: December 2021

Background

Longitudinal changes in volume using co‐registration of two serial T1W MRI scans are used as biomarkers to track the development of Alzheimer’s Disease and monitor potential treatment effects. Current methods (e.g., the boundary shift integral, BSI) may be restricted to certain regions or are computationally intensive and slow (e.g., the Advanced Normalization Tools, ANTs).

Method

We present an AI‐based framework to calculate voxel‐wise atrophy in the human brain. Our method features convolutional neural networks for cross‐sectional semantic segmentation and longitudinal pairwise non‐linear registration which does not require subject‐specific optimization. It warps one image to another by minimizing their difference, while preserving topology. Voxel‐wise volume change is estimated using the Jacobian determinant of the warp field, summed within a specified and automatically segmented region of interest in the baseline image. We evaluate our framework in ADNI (40 HC and 40 MCI) and OASIS3 (100 HC and 100 MCI) participants and assess the method’s measures of annualized atrophy in whole brain, ventricles, and hippocampus using common language effect sizes (CLES) and a Mann‐Whitney U‐test. Retest variability is measured in 30 OASIS3 participants with two serial MR scans not more than 13 days apart. We compare results to BSI as well as the same framework but substituting the non‐linear registration part with ANTs.

Result

Our algorithm outperforms ANTs in non‐linear registration accuracy with mean (SD) normalized mutual information of 0.746 (0.055) compared to 0.651 (0.052) for ANTs and 0.646 (0.049) with affine registration only. It also has lower retest variability than ANTs (mean variability range is 0.08%‐0.12% and 0.15%‐0.34% for our algorithm and ANTs respectively). Finally, both BSI and our method show significant group difference for whole brain, ventricles, and hippocampus (all p < 0.002, CLES > 0.69) in both datasets, whereas in ANTs there is no significant group effect for hippocampus (p = 0.12) (see Table 1 for all results).

Conclusion

Our framework produces fast (seconds) and accurate non‐linear registration and voxel‐wise atrophy calculation for two serial MR images. Our calculated atrophy values show sensitivity to clinical diagnosis in cognitively impaired patients, comparable to current state‐of‐the‐art methods.
Mid‐life epigenetic age, neuroimaging brain age, and cognitive decline: Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Zheng Yinan , Habes Mohamad , Gonzales Mitzi M. , Pomponio Raymond , Nasrallah Ilya M. , Davatzikos Christos , Seshadri Sudha , Launer Lenore J. , Sorond Farzaneh , Sedaghat Sanaz , Bryan Nick , Sidney Stephen , Yaffe Kristine , Baccarelli Andrea , Hou Lifang
Published: December 2021

Background

Establishing biological aging markers that predict cognitive performance may aid early identification of individuals at risk for accelerated cognitive decline and promote the development of interventions to preserve optimal cognitive function across the lifespan. We investigated two distinct classes of biological aging markers, 1) epigenetic aging, an emerging class of blood‐derived DNA methylation markers that aggregate aging‐related DNA methylation information; and 2) Spatial Patterns of Abnormality for Recognition of Brain Aging (SPARE‐BA), a composite magnetic resonance imaging (MRI) index of brain aging.

Method

We evaluated the cross‐sectional and prospective associations between both classes of aging markers and cognitive performance across a 15‐year follow‐up in the biracial CARDIA cohort of approximately 1,000 middle‐aged adults, using multiple linear regression and logistic regression. We compared the diagnostic performance of both aging markers using receiver operating characteristic (ROC) curve analysis.

Result

We found that accelerated epigenetic aging and brain aging were both cross‐sectionally and prospectively associated with worse cognitive outcomes. Specifically, every 5‐year faster epigenetic/brain aging is on average associated with 9.7% standard deviation (SD) higher in Stroop Test score, 7.7% SD lower in Rey Auditory Verbal Learning Test score, and 10.3% SD lower in Digital Symbol Substitution Test (all false‐discovery‐rate‐adjusted p <0.05). ROC analysis showed that a combined model with both epigenetic aging and brain aging markers optimized discriminability of individuals with lower cognitive performance 5 to 10 years later (area under the ROC curve: 0.70; 95% confident interval: 0.63‐0.77, Figure). Epigenetic and brain aging markers were weakly correlated with one another (Person’s r =0.17) and not statistically significant.

Conclusion

Our results showcase the significance of novel biological aging markers for cognitive health. Accelerated epigenetic aging and brain aging may capture distinct facets of biological aging and may jointly serve as early indicators of future cognitive decline and inform early interventions to prevent or delay cognitive impairment.
The (non)sense of diagnostic computer tools in memory clinics: An international survey assessing the views of clinicians, patients and caregivers
Authors: Van Gils Aniek M , Visser Leonie N.C. , Hendriksen Heleen M.A. , Georges Jean , Muller Majon , Bouwman Femke H. , van der Flier Wiesje M , Rhodius‐Meester Hanneke FM
Published: December 2021

Background

Computer tools aid clinicians by combining test results and facilitating interpretation, in reaching decisions and communication, on both diagnosis and prognosis. Nevertheless, to date, such tools are hardly used in daily clinical practice. To optimally meet the needs of end‐users, as a prerequisite for further development and implementation of computer tools, we set out to identify barriers and facilitators for the use of computer tools in memory clinics according to clinicians. In addition, we aimed to synthesize the opinions of patients and caregivers about this topic.

Methods

Between July and October 2020, 109 European clinicians (45±10y, 49% F) completed an online survey on their views regarding the use of diagnostic and prognostic tools. Questions related to the willingness of using tools and factors that would hinder or stimulate the use. Furthermore, 50 European patients with SCD, MCI or dementia (73±8y, 34% F) and 46 caregivers (65±12y, 54% F) completed an alternative survey focused on their opinion.

Results

The vast majority of clinicians reported a willingness to use diagnostic (80%) and prognostic (77%) computer tools. Increasing diagnostic accuracy was reported as the main factor to stimulate the use of a tool. In addition, clinicians indicated that tools should be easy to understand, time‐saving, and providing clear information on reliability and validity (Fig 1). Inadequate integration with electronic patient files and fear of losing important clinical information were most frequently indicated as barriers (Fig 1). Patients and caregivers were also positive about the use of computer tools by clinicians, both for diagnosis (71%) and prognosis (77%). They viewed computer tools as an addition to the current way of working, appropriate to modern times (Fig 2).

Conclusion

This study shows that most end‐users are in favor of using computer tools in memory clinics, for diagnosis and prognosis. In order to stimulate implementation of computer tools, it is key to maximize the extracted information and to optimize integration with electronic patient files, while simultaneously provide clear information about reliability and validity. These insights pave the way for the further development of computer tools that meet the needs of end‐users and, consequently, successful implementation.
Alzheimer’s Disease (AD): Sarcopenia is associated with lower Mini‐Mental State Exam (MMSE) scores
Authors: Komatsu Caroline , Komatsu Ricardo S , Ariosa Rodrigo Hara , Sipioni Micheli
Published: December 2021

Background

Sarcopenia is highly prevalent in dementia, regardless of sarcopenia definition and irrespective of continent of study. According to the systematic review and meta‐analysis conducted by Chang et al. (2016), sarcopenia is independently associated with cognitive impairment.

Methods

195 outpatients with the diagnosis of AD conforming to criteria proposed by NINCDS‐ADRDA (2011), followed‐up at a public university hospital, had their sarcopenia levels assessed in consonance with the European Working Group on Sarcopenia in Older People (EWGSOP) and MMSE scores evaluated.

Results

55 out of 195 patients (28,20%) were diagnosed with sarcopenia (Low Mass Muscle ‐ LMM plus Low Muscle Strength – LMS or Low Physical Performance – LPP). From the sarcopenia group 4 patients (7,28%) presented severe cognitive impairment (MMSE < 10), 25 patients (45,45%) presented moderate cognitive impairment (MMSE = 10 – 20) and 26 patients (47,27%) presented mild cognitive impairment (MMSE > 20). From the non‐sarcopenia group 11 patients (7,86%) presented severe cognitive impairment, 45 patients (32,14%) presented moderate cognitive impairment and 84 patients (60%) presented mild cognitive impairment. Both groups, sarcopenia and non‐ sarcopenia, had on average the same educational level: 2,93 and 3,66 years respectively.

Conclusion

In this sample of patients with AD, sarcopenia is associated with lower MMSE scores when compared to non‐sarcopenia.
The first female engineer at General Motor’s descent into Alzheimer’s with sundowners: A daughter’s scholarly research and case study as caregiver
Authors: Keely Amy J
Published: December 2021

Background

Alzheimer’s with Sundowners continues to be one of the greatest challenges between the patient and caregiver. Sundowners familial caregivers are often reluctant to place their loved one’s into facilities in part due to the stigma around the aggressive behaviors and also concerns about the care their loved one will receive.

Methods

In a comparative analysis between my grandmother who had Alzheimer’s and my mother with Alzheimer’s with Sundowners, there are key differences supporting the behavioral nature of Sundowners from my mother's diagnosis in 2014. Investigations into the emerging research around dementia lucidity, is confirmed by levels of ‘awareness’ my mother had until her death in February 2020. Research captures levels of caregiver burnout and the types of tools for long‐term facilities to demarcate between ‘traditional’ Alzheimer’s and Sundowners. This behavioral research includes videos, caregiver case studies, and cognitive decline shown through artwork, that will provide evidence that dementia lucidity causes Sundowners behavior issues as patients are aware, scared, and terrified of an increasingly confusing world.

Results

Behaviorally “difficult” patients – like my mother – continue to be treated with ‘chemical restraints’ offered by harsh off label anti‐psychotic drugs with FDA black box warnings that are burning through their remaining delicate synapses. Training is required to provide Sundowner patients with a higher level of engagement. Treatment at earlier stages should include testing for melatonin/serotonin levels for treatment, different applications of music/light therapy, Art therapy, CBD/THC treatment, and behavioral redirects to keep Sundowners patients calm.

Conclusion

Quarterly online self‐directed training with assessment scoring and gamification will help embed behavioral redirects techniques (especially during the first six months at a facility) and support distressed families. Better levels of engagement results in calmer patients so they can have greater dignity as they go through the final throws of brain death. ‘I need to go home”, isn’t a physical place where they want to go, but a cry for help to find a mental place of comfort ‐ just as a child reaches for a favorite blanket – and we owe them that place of peace.
Sleep characteristics associated with mild cognitive impairment among rural‐dwelling older adults: The MIND‐China study
Authors: Liu Rui , Tang Shi , Ren Yifei , Wang Yongxiang , Cong Lin , Du Yifeng , Qiu Chengxuan
Published: December 2021

Background

Sleep characteristics associated with mild cognitive impairment (MCI) and its subtypes are poorly defined in old age. We sought to characterize the sleep disturbances associated with MCI, subtypes of MCI, and specific cognitive domains among rural‐dwelling older adults in China.

Method

This population‐based cross‐sectional study included 4469 participants (age ≥65 years, 56.4% women) who were free of dementia and living in the rural communities in Yanggu County, Shandong. We collected data through interviews, clinical examinations, neuropsychological testing, and laboratory tests. We used the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale to evaluate various sleep parameters. Specific domain of cognitive function were assessed with the Auditory Verbal Learning Test (immediate recall, long‐delayed free recall, and long‐delayed recognition) for memory, the Semantic Verbal Fluency Test for language, the Digit Span Test for attention, and the Trail Making Test A & B for executive function. MCI was diagnosed according to the Petersen’s criteria. Data were analysed using logistic and general linear regression models.

Result

MCI was diagnosed in 1204 participants (940 with amnestic MCI [aMCI], 264 with nonamnestic MCI [naMCI]). The multivariable‐adjusted odds ratio (OR) of MCI was 1.45 (95% CI 1.14‐1.83) for sleep duration ≤4 hours/night (vs. >6‐8 hours/night), 1.39 (1.12‐1.72) for sleep duration >8 hours/night, 1.23 (1.06‐1.43) for poor sleep quality, 1.46 (1.25‐1.70) for low sleep efficiency, 1.29 (1.10‐1.50) for prolonged sleep latency, and 1.49 (1.17‐1.88) for excessive daytime sleepiness (EDS). These sleep characteristics were significantly associated with aMCI (multi‐adjusted OR range: 1.27‐1.46; p<0.05). EDS was significantly associated with naMCI (multi‐adjusted OR 1.56 [1.04‐2.33]). In addition, short and long sleep duration, poor sleep quality, low sleep efficiency, prolonged sleep latency, and EDS were associated with worse memory function. Long sleep duration, low sleep efficiency, and EDS were associated with worse language function. Low sleep efficiency and EDS were associated with worse attention function. However, none of the examined sleep parameters was significantly associated with executive function.

Conclusion

Short and long sleep duration, poor sleep quality, low sleep efficiency, prolonged sleep latency, and EDS were associated with an elevated likelihood of MCI, especially aMCI and poor memory function.
Novel use of tau imaging to enrich for pathological homogeneity within the PERISCOPE‐ALZ study of zagotenemab
Authors: Munsie Leanne M , Lo Albert C. , Fleisher Adam S , Andersen Scott W. , Shcherbinin Sergey , Sims John R. , Brys Mirek , Mintun Mark A
Published: December 2021

Background

Zagotenemab (LY3303560), a humanized monoclonal antibody targeting extracellular aggregated tau, is currently in development as a potential disease modifying treatment for early symptomatic Alzheimer’s disease (AD). The PERISCOPE‐ALZ study (Phase 2, NCT03518073) of zagotenemab implements tau PET for classifying AD pathological stage based on the NIA‐AA guidelines (Jack CR, Jr., Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535‐62) and serves as a key eligibility criterion. Here we summarize the study’s screening and baseline characteristics.

Method

Screening procedures were performed at 60 sites in the United States, Canada, and Japan. Key eligibility criteria include age of 60‐85 years, Mini‐Mental State Exam (MMSE) score of 20‐28, and pre‐defined baseline tau load as assessed by flortaucipir F18 PET. This eligibility strategy was intended to exclude participants with minimal tau burden whose pathology may not be consistent with AD in absence of amyloid pathology confirmation and who are expected to have slower clinical progression. Participants with high tau levels, hypothesized to be less likely to respond to therapy, were also excluded.

Result

The most common reasons for screen failure were out of range baseline tau levels and cognitive screener score. Of screened participants who underwent a flortaucipir scan, 58% did not meet scan eligibility criteria. Seventy‐nine percent of the flortaucipir scans not meeting eligibility criteria were below pre‐defined tau levels required for inclusion. A higher proportion of females than males who were ineligible based on the tau scan harbored too high of tau levels for eligibility (27% v. 14%, chi‐square p=0.0004). The enrolled cohort had an average age at baseline of 75 years and 53% were female. Average MMSE score at baseline of the enrolled cohort was 23.7.

Conclusion

PERISCOPE‐ALZ successfully implemented flortaucipir PET imaging as the key inclusion criterion to enroll a pathological homogeneous cohort based on level of tau accumulation. As tau‐targeted therapies for AD advance into clinical research, staged tau pathology as eligibility criterion may be useful in phase 2 proof‐of‐concept trials to test disease modifying therapies. Topline trial results are anticipated in late 2021.
Hospital readmissions following infections in dementia: A nationwide and registry‐based cohort study
Authors: Janbek Janet , Frimodt‐Møller Niels , Laursen Thomas Munk , Waldemar Gunhild
Published: December 2021

Background

Unplanned acute hospital readmissions put persons with dementia at risk for adverse health outcomes. It is crucial to identify avenues for effective interventions to decrease or prevent unnecessary readmissions, especially in particularly vulnerable patient groups such as those living with dementia and particularly for common and potentially preventable reasons for hospitalization such as infections. Relatively little is known about hospitalization trajectories for people with dementia who get admitted to a hospital with an infection, and surprisingly little is described and documented in literature. We aimed to investigate readmission risks (with dementia and without); identify types of infections behind risks; and highlight reasons for readmissions.

Method

Registry‐based cohort of elderly patients with acute inpatient hospital admissions for infections in Denmark included from January 1, 2000 or age 65 years. Primary outcomes: 7‐day readmissions (Risk Ratios [RR]: Risk following index admissions with dementia relative to without); risks by infection site, and reasons for readmission (secondary: 30‐ and 90‐day readmission). Competing risk of death was estimated.

Result

789,732 index admissions (421,133 people) were included and resulted in 55,303 readmissions in 7 days (10% followed admissions with dementia) and 78,732 deaths (14% followed admissions with dementia). Readmission and mortality RRs were higher following index admissions for infections than for other causes. Seven‐day readmission RR was increased in all ages and highest in the youngest (Women RR 1.37, 95% confidence interval [CI] 1.22‐1.53; Men RR 1.23, 95% CI: 1.12‐1.35). RRs reduced with increasing age and longer follow‐up (where some were insignificant or decreased). Readmission risks were notably higher following admissions with dementia in the youngest ages in all infection sites, and reasons for readmission varied by infection site and were most commonly due to infection (either linked/unresolved or other infection) and dehydration.

Conclusion

Findings highlight need for improvements in preventing and treating infections in people with dementia, and in ensuring successful transition from the hospital to the community that includes individualized care and close follow‐up by caregivers and skilled health personnel. In‐depth investigations of determinants related to readmission risk are needed, to highlight important avenues for interventions to decrease or prevent potentially avoidable readmissions.
More than a memory test: A new metric linking blocks, numbers, and words
Authors: Melin Jeanette , Cano Stefan , Flöel Agnes , Göschel Laura , Pendrill Leslie ,   EMPIR NeuroMET and NeuroMET2 consortiums
Published: December 2021

Background

The extent to which existing legacy memory tests are accurate and sensitive in detecting early cognitive decline is questionable. This reflects the wider picture in neurodegenerative conditions where clinical rating scales have not been developed for early‐stage disease. Item banks delivered through computer adaptive tests can help. But, in order to be fit‐for‐purpose, this approach requires a metrological framework with recourse to units, traceability, and interoperability. Here we describe the initial research to build such an item bank, based on legacy tests.

Method

Memory tests (i.e., Corsi Block Test [CBT], Digit Span Test [DST], Rey’s Auditory Verbal Learning Test [RAVLT] and Word Learning List [WLL]) data were collected in the European EMPIR NeuroMET and the SMART cohorts recruited in Charité Hospital (Healthy control n 86; Subjective Cognitive Decline n 99; Mild Cognitive Impairment n 37; and Alzheimer’s Disease n 45). In order to align with metrological requirements, Rasch measurement theory in conjunction with construct specification equations were chosen to analyse the data.

Result

Based on the combined dataset, when analyzed on their own, the data from the CBT, DST, RAVLT and WLL revealed skewness, gaps, and large measurement uncertainties. The addition of items from each of the tests into a bank improved these psychometric issues, improving reliability from a minimum of 0.65 to 0.85. The metrological legitimization of the ‘NeuroMET Memory Metric’ (formed from the combination of items) was confirmed through construct specification equations, which provided a Pearson correlation coefficient for empirical values vs. predicted (zR) values of up to 0.98 for task difficulty.

Conclusion

Our early promising findings provide a strong foundation for a metric of memory ability, which can be used as the basis for computer adaptive testing, better targeted measurement, and more accurate discrimination of early cognitive decline. Establishing units can also provide for the potential of developing crosswalks between a wider range of memory test items. Further work includes further longitudinal data collection to confirm item estimates, development of a digital platform, and a quality assurance program to establish traceability, and interoperability.
Artificial Intelligence empowered recruitment for clinical trials
Authors: Linz Nicklas , ter Huurne Daphne BG , Langel Kai , Ramakers Inez HGB , König Alexandra ,   DeepSpA
Published: December 2021

Background

Recruitment of clinical drug trials for Alzheimer's disease (AD) is a lengthy process with an ultimately high screening failure rate, as current research focuses on prodromal stages. We evaluate the option of pre‐screening potential participants for AD trials via an automated phone‐based assessment using speech analysis.

Method

140 participants were recruited at the memory clinic in Maastricht as part of the MUMC+ study (SCI, MCI, ADD). They underwent a in‐person baseline assessment (0M) at the clinic. Cognitive assessments were performed and speech was recorded during each assessment using the Delta platform. For the next assessments (6M), participants were contacted via telephone by a trained research nurse. Cognitive assessments were performed on the phone and speech was recorded during each assessment. Speech from each assessment point was analysed automatically to extract relevant features. Machine learning models to predict disease status, Clinical Dementia Rating Scale (CDR) scores, and Mini‐Mental‐Status‐Examination scores were trained and evaluated on the data.

Result

Models based on speech features extracted from the phone assessment were able to predict disease status with an AUC of 0.93±0.06, CDR score with a Mean Absolute Error (MAE) of 1.9±0.8, and MMSE score with an MAE of 2.3±1.1. Adding longitudinal data from baseline assessments increased accuracy across all models.

Conclusion

Automated pre‐screening through speech analysis could be an effective tool to increase the efficiency and effectiveness of recruitment for AD drug trials.
Motor proficiency composite scores as a novel biomarker for Alzheimer's disease
Authors: Koppelmans Vincent , Ruitenberg Marit F.L. , Van der Geest Jos , Duff Kevin M.
Published: December 2021

Background

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are associated with various motor impairments in ambulatory and manual measures that involve speed, force, and precision. Prior studies suggest that such motor impairments are an early disease marker and predict AD progression. A composite motor score that combines motor measures spreading the breadth of motor domains could be a stronger predictor than individual motor measures. Here, we evaluate associations of motor composite scores with existing AD biomarkers in a combined group of individuals with MCI and AD, and cognitively normal individuals.

Method

All participants, who were classified by ADNI‐2 criteria, completed the following motor measures: 1) grip strength using a hand‐dynamometer; 2) general motor reaction time assessed as the time between the visualization of stimuli on a computer screen and pressing a button; 3) psychomotor speed using the Trail Making Test Part A; 4) unimanual and bimanual finger tapping speed using a keyboard; and 5) drawing speed and accuracy using the computerized Archimedes spiral tracing test. Motor composite scores were defined as the sum of the z‐transformed raw measures. Additionally, participants underwent APOE genotyping to determine the presence of e4 alleles, amyloid PET imaging to quantify amyloid deposition, and structural MRI scanning to obtain hippocampal volume. Correlational analysis was used to test the association between motor composite score and AD biomarkers.

Result

To date, 5 cognitively normal, 7 MCI, and 9 AD subjects completed all assessments. Motor composite scores were significantly and strongly associated with AD biomarker scores (p<.05 and Cohen's d>.8 for all outcomes; see Figure 1). Individuals with more APOE e4 alleles had worse motor composite scores (Rho=‐0.43). Higher amyloid burden was related to worse motor composite scores (r=‐0.51). Larger volume of the left hippocampus correlated with better motor composite scores (r=0.51).

Conclusion

Motor proficiency, as reflected in composite scores, is strongly associated with established markers of AD. Ongoing work focuses on expanding our sample size to allow for statistical correction for potential confounders such as age, stratify the sample to study potential sex differences, and compare motor scores to neuropsychological test scores collected in this sample.
Association of antiherpetic medication with incident dementia in Denmark, Wales, Germany and Scotland
Authors: Schnier Christian , Janbek Janet , Williams Linda , Wilkinson Tim , Laursen Thomas Munk , Waldemar Gunhild , Richter Hartmut , Kostev Karel , Lathe Richard , Haas Juergen
Published: December 2021

Background

Several epidemiological studies from Taiwan, all using the same data resource, found significant associations between herpes virus infection, antiherpetic medication and dementia. We conducted a multicenter observational cohort study using health registry data from Wales, Germany, Scotland, and Denmark to investigate potential associations between antiherpetic medication and incident dementia, and also to comprehensively investigate such associations broken down according to medication type and dose, type of herpes virus, and dementia subtype.

Method

2.5 million people aged 65 and older were followed up using routinely collected linked electronic health records in four separate national observational cohort studies. Exposure and outcome were classified using coded data from prescriptions and from primary and secondary care. Data were analyzed using survival analysis with time‐dependent covariates. Confounders were age, year, sex, socioeconomic status, and comorbidities.

Result

Results were heterogenous across cohorts (Figure 1), with a tendency for decreased dementia risk in people exposed to antiherpetic medication (Wales: HR 0.91, 95% CI 0.86 to 0.97; Denmark: HR 0.91 (0.89 to 0.93); Germany: HR 1.08 (0.98 to 1.20); Scotland: HR 0.98 (0.64 to 1.49). Associations were not affected by number of treatments, herpes diagnosis, type of dementia, or specific type of medication. People diagnosed with herpes but not exposed to antiherpetic medication were at higher dementia risk in the German cohort (HR: 1.18; 1.09 to 1.28) but not in the Welsh cohort (HR: 0.95; 0.88 to 1.02).

Conclusion

Results from the four large cohorts allow us to exclude any major association of short‐term exposure to antiherpetic medication with dementia. Because neither type of dementia nor type of herpes infection modified the association, the small but significant decrease in dementia incidence with antiherpetic administration mayeflect unmeasured confounding and misclassification.
Muscular function: An alternative way to identify cognitive impairment—secondary analysis from SABE‐Colombia
Authors: Garcia‐Cifuentes Elkin , Botero‐Rodríguez Felipe , Velandia Felipe Ramirez , Iragorri Angela , Márquez Isabel C , Gelvis Geronimo , Acosta Maria‐Fernanda , Jaramillo‐Jimenez Alberto , Lopera Francisco , Cano‐Gutierrez Carlos Alberto
Published: December 2021

Background

Traditionally, the identification of cognitive impairment is based on neuropsychological tests and supported with not widely available biomarkers. This study aimed to establish the association between motor function (Gait Speed and Handgrip Strength) and the performance in a global cognitive performance and various cognitive domains. Our secondary objective was to determine a cut‐off point for Gait Speed and Handgrip Strength to classify older adults as cognitively impaired.

Method

This is a secondary analysis from the SABE Colombia study (Health, Well‐Being, and Aging) conducted in 2015. We performed linear regression models, to establish association with motor function, clinical, and sociodemographic variables, and predict the scores of the Mini‐mental State Examination and its domains (i.e. orientation, recall, counting, and language). The evaluation of the motor function variables as an instrument to separate cognitively impaired older adults was evaluated by developing a receiving operating characteristic curve (ROC).

Result

Gait speed was associated with orientation (r2 = 0.16), language (r2 = 0.15), recall memory (r2 = 0.14) and counting (r2 = 0.08). Similarly, handgrip strength was associated with orientation (r2 = 0.175), language (r2 = 0.164), recall memory (r2 = 0.137), and counting (r2 = 0.08). Slow gait had a cut‐off point of 0,59 m/s, with an area under the curve (AUC) of 0.629 (0.613‐0.646), whereas a weak handgrip strength had an AUC of 0.653 (0.645‐0.661), with a cut‐off point of 17.50 Kg for separating those older adults with cognitive impairment.

Conclusion

Gait Speed or Handgrip Strength are similarly associated with cognitive performance, exhibiting the larger associations with orientation and language domains. Gait Speed and Handgrip Strength can be easily performed by any clinician and seems to be useful screening tools to detect cognitive impairment.