bluuebunny/crossref_metadata_2025 huggingface dataset:
Arabic translation and cross‐cultural adaptation of the Bristol Activities of Daily Living Scale (BADLS)
Authors: Alkeridy Walid Ahmed , Muayqil Taim A , Al Khalifah Reem Abdullah , Mohammedin Ahmed S , Khallaf Roaa A. , Bucks Romola S
Published: December 2021

Introduction

The prevalence of dementia is expected to increase exponentially in developing countries over the next few decades.1, 2 Arabic language is widely spoken across the middle east and north Africa, where dementia diagnosis remains challenging.3 Many factors contribute to the underdiagnosis of dementia in Arabic speaking countries including the lack of validated functional assessment tools for patients with cognitive impairment.2, 4 The aim of this study is to translate, cross culturally adapt and validate the widely used Bristol Activity Of Daily Living Scale (BADLS)5 to the Arabic language.

Methods

First the BADLS was translated to the Arabic language by two independent bilingual experts. The Arabic version was then back translated to English by two independent translators. Then reviewed by expert panel including the original author to keep original meanings, check accuracy and standardization. A pilot study was done for Cognitive Debriefing. Expert panel discussion was done to review cognitive debriefing and finalize. Criterion validity is tested against the validated Arabic version of the Katz Index of Independence in Activities of Daily Living and the Arabic version of the Montreal Cognitive Assessment (MOCA) test.

Conclusion

To our knowledge this is the first study to translate the BADLS to the Arabic language. The Arabic BADLS will enable the early and accurate diagnosis of dementia for Arabic speaking patients and caregivers. References: 1. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396(10248):413‐446. 2. Epidemiology of Alzheimers Disease and Dementia in Arab Countries: A Systematic Review. Behavioural Neurology. 2019. 3. Benabdeljlil M. Assessment of cognitive disorders in the Arabic language. Journal of the neurological sciences. 2019;405(S):66‐67. 4. Abou‐Mrad F, Chelune G, Zamrini E, Tarabey L, Hayek M, Fadel P. Screening for dementia in Arabic: normative data from an elderly Lebanese sample. The Clinical Neuropsychologist. 2017;31(sup1):1‐19. 5. Bucks RS, Ashworth DL, Wilcock GK, Siegfried K. Assessment of Activities of Daily Living in Dementia: Development of the Bristol Activities of Daily Living Scale. Age Ageing Age and Ageing. 1996;25(2):113‐120.
Tau deposition is associated with grey matter network breakdown across different stages of the Alzheimer’s disease continuum
Authors: Pelkmans Wiesje , Ossenkoppele Rik , Dicks Ellen , Strandberg Olof , Barkhof Frederik , Tijms Betty M. , Pereira Joana B. , Hansson Oskar
Published: December 2021

Background

Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer’s disease (AD), and have been associated with amyloid‐β (Aβ) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau‐related connectivity changes across different stages of AD might be expected.

Method

In this study, we examined the relationship between tau aggregation (using tau positron emission tomography [tau‐PET]) and grey matter networks (using T1‐weighted images) in 533 individuals (178 Aβ‐negative cognitively unimpaired (CU) subjects, 105 Aβ‐positive CU subjects (preclinical AD), 122 Aβ‐positive patients with mild cognitive impairment (prodromal AD), and 128 patients with AD dementia) from the Swedish BioFINDER‐2 study (Table 1). Single‐subject grey matter networks were extracted and graph theory properties including degree, connectivity density, clustering coefficient, path length, and small world topology were calculated. Associations between tau‐PET values and global and regional network measures were examined using linear regression models adjusted for age, sex, total intracranial volume, and connectivity density.

Result

Across the whole sample, we found that higher tau load in the temporal meta‐ROI was associated with significant changes in degree, connectivity density, clustering, path length, and small world values of the brain network (all p < 0.001; Fig. 1, 2), indicative of a less optimal network organization. Already in early disease stages, higher tau PET signal was associated with lower clustering and path length (Table 2). In more advanced disease stages elevated tau pathology was progressively associated with more advanced brain network abnormalities.

Conclusion

These findings suggest that tau pathology is associated with a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions indicative of a more random network topology across different AD stages.
Identifying cognitive trajectories and predicting rapid decline of cognitive function in early Alzheimer’s disease
Authors: Lin Yung‐Shuan , Fuh Jong‐Ling
Published: December 2021

Background

The clinical manifestations and progression of cognitive function vary between patients with Alzheimer disease (AD) and mild cognitive impairment (MCI). Predicting disease course is important for families and clinicians because most patients experience progressive and irreversible cognitive decline despite variations.

Methods

This study sought to identify groups of patients following a similar trajectory of cognitive decline over time, and then developed a prediction model to identify patients at higher risk for a speedy cognitive decline. This study was conducted on a clinic‐based cohort of 233 early AD and MCI patients who converted to AD within 2 years in Taiwan. A group‐based trajectory modeling technique characterized the trajectory groups of Mini‐Mental State Examination (MMSE) scores over time. Feature‐selection strategy was then used to investigate predictors of the trajectory of rapid cognitive decline. Finally, multivariable logistic regression (LR) was applied to predict the trajectory group membership from the predictors.

Results

The best‐fitting model includes two meaningful trajectories: Group 1 shows a rapid decline in the MMSE scores over time (decrease of 5.4±3.9 points within 2 years); Group 2 shows a slow progression (decrease of 1.2±3.9 points within 2 years). The baseline MMSE score, instrumental activities daily living (IADL) total score, and APOE ε4 status are significant predictors in the prediction model for classifying the trajectory of cognitive decline. After bootstrapping validation, the performance of the LR model using these predictors to predict trajectory groups shows 85.3% of area under curve (AUC), 79.0% of sensitivity, 73.1% of specificity, and 75.4% of predictive accuracy.

Conclusions

Among various biomarkers and neuropsychological battles for patients with AD or MCI, baseline MMSE score, IADL total score and APOE ε4 status are the ones important and unchallenging to obtain in dementia clinics. The LR model for the prediction model is easy to understand and apply in the clinical practice. This model gives clinicians and patients a glimpse of future cognitive progression and aids further healthcare planning.
An individualized systems model to optimize Alzheimer’s disease prevention strategies
Authors: Uleman Jeroen F , Quax Rick , Melis René JF , Hoekstra Alfons , Rikkert Marcel GM Olde
Published: December 2021

Background

A large number of biopsychosocial factors are implicated in the prevention of Alzheimer’s Disease (AD). These factors are not independent causes but part of a complex causal network that underlies the condition. Computational models that would capture this system‐wide multicausality could help identify causal pathways and inform multifactorial prevention strategies.

Method

We developed a system dynamics model (SDM) from a causal loop diagram that was parameterized using empirical data from multiple cohorts (including the Alzheimer’s Disease Neuroimaging Initiative). The SDM contains over 20 known risk factors and pathophysiological processes, including blood pressure, smoking, neuronal dysfunction, and amyloid‐beta and phosphorylated tau burden. We simulated 5‐year cognitive decline trajectories for individuals and explored several “what if” scenarios regarding the effect of changes in modifiable risk factors on cognitive decline.

Result

Our SDM was able to simulate the cognitive decline trajectories of individuals with good accuracy (< 20% mean absolute percentage error). These predictions also generalized well to an independent test sample from the same data set (<2% error increase). The effect of changes in modifiable risk factors on cognitive decline in the SDM were checked against literature reported ranges. We also developed a workflow to further calibrate and validate the SDM.

Conclusion

Our SDM demonstrates the feasibility of system‐wide modelling approaches for AD prevention. Such a simulation model could eventually be used to better understand the interactive effects of modifiable risk factors on AD pathophysiology and help optimize individualized prevention strategies.
Development of a tool to motivate for healthy behaviors to prevent dementia in Cuba, Puerto Rico and Dominican Republic
Authors: Peeters Geeske , Almirall‐Sanchez Arianna , Llibre‐Guerra Jorge J , Jiménez‐Velazquez Ivonne Z , Acosta Daisy M , Lawlor Brian , Anne Kenny Rose , Yaffe Kristine , Llibre‐Rodriguez Juan J
Published: December 2021

Background

Previous research showed that up to 56% of all dementia cases in Latin America could potentially be prevented if all modifiable risk factors were eliminated. Trends of studies in Latin America show, however, that lifestyles are declining. In absence of a cure, prevention is crucial. The aim was to develop a tool that can be used in primary care settings to raise awareness for modifiable risk factors and motivate high‐risk individuals to adopt healthy lifestyles to reduce their risk of dementia.

Method

Data were from the Cuban (n=1846, mean age=73.9 ±6.4), Dominican Republic (DR, n=1053, mean age=76.3 ±6.8) and Puerto Rican (PR, n=1166, mean age=76.3 ±7.4) cohorts of the 10/66 Dementia Research Group. Participants completed questionnaires, health examination and cognitive tests at baseline and on average 4.5‐5 years later. Logistic regression was used to identify key modifiable risk factors. The 3 or 4 most important modifiable risk factors were combined into a grid and cells were colour coded to display the levels of risk according to absolute proportions of incident dementia (green/low: <9%, yellow/medium: 9‐<13%, orange/high: 13‐<20%, red/very high: >20%).

Result

Physical activity, hypertension and diet were identified as the key modifiable risk factors. Hence, the grid included hypertension (yes/no), diet (composite measure of regular/no fish consumption and <4/4+ serves of vegetables) and physical activity (high, moderate, low) only. The levels of risk varied from low (6.6%) in participants with none of the risk factors to high (18.5%) in participants with all three risk factors. The highest risk was found in participants who were inactive and did not eat fish (24.8%).

Conclusion

We have developed a tool that visualises the levels of risk and how each risk factor contributes to the risk of dementia. It also shows how one may lower their risk by addressing the risk factors. The tool can be used in primary care settings to motivate people for adopting healthy behaviours.
Impact of APOE and BDNF Val66Met polymorphisms on spatial navigation and brain morphometry in subjective cognitive decline
Authors: Laczó Jan , Cechova Katerina , Parizkova Martina , Lerch Ondrej , Matoska Vaclav , Kaplan Vojtech , Matuskova Veronika , Markova Hana , Nedelska Zuzana , Vyhnalek Martin , Hort Jakub
Published: December 2021

Background

The apolipoprotein E (APOE) ɛ4 allele is associated with episodic memory deficits, less accurate spatial navigation and hippocampal atrophy in nondemented older adults. The brain‐derived neurotrophic factor (BDNF) Met allele may further worsen memory impairment and reduce hippocampal activation in APOE ɛ4 carriers but its role in APOE ɛ4‐related spatial navigation deficits has not been established. We aimed to evaluate the influence of combination of the APOE and BDNF Val66Met polymorphisms on spatial navigation, cognitive functions and volumes of selected brain regions associated with spatial navigation including the hippocampus, entorhinal cortex, precuneus, inferior parietal and posterior cingulate cortex in individuals with subjective cognitive decline (SCD).

Method

In total, 71 older adults with SCD from the Czech Brain Aging Study were stratified based on the APOE and BDNF Val66Met polymorphisms into four groups: ɛ4–/BDNF
Val/Val (n =27), ɛ4–/BDNF
Met (n = 15), ɛ4+/BDNF
Val/Val (n =18), and ɛ4+/BDNF
Met (n=11). The participants underwent comprehensive neuropsychological examination, brain MRI and spatial navigation testing of egocentric, allocentric, and allocentric delayed navigation in a real‐space human analogue of the Morris water maze.

Result

The ɛ4+/BDNF
Met group, although similar to other polymorphism groups in age, gender, education, depressive symptoms and global cognitive function, had less accurate allocentric and allocentric delayed navigation performance than the ɛ4–/BDNFVal/Val group (p<0.05). There were no significant differences in egocentric navigation performance, cognitive performance in any cognitive domain including attention and working memory, nonverbal memory, executive function, language and visuospatial function and volumes of selected brain regions associated with spatial navigation between the polymorphism groups (p>0.05).

Conclusion

Individuals with SCD and the high risk combination of APOE ɛ4 and BDNF Met alleles had less accurate allocentric spatial navigation than those with the low risk combination of APOE ɛ3 and BDNF Val alleles. This finding may indicate that individuals with SCD and two high risk gene polymorphisms are particularly susceptible to hippocampus‐dependent spatial navigation deficits and may be at greater risk of cognitive decline and progression to mild cognitive impairment. Our results also suggest that spatial navigation testing could more reliably assess the deleterious effect of the BDNF Met allele on cognition than other cognitive tests.
In vivo imaging of LC‐NE Integrity: Mechanism for racial/ethnic disparity in preclinical AD
Authors: Ding Yu‐Shin , Wang Jiacheng , Rusinek Henry , Babb James
Published: December 2021

Background

Despite studies suggesting that blacks may be at greater risk of developing AD, there have been few studies investigating health disparities, and blacks have been underrepresented in many prominent AD biomarker studies and clinical trials. The current ATN biomarker classification system may not fully account for health disparities and can’t explain the increased prevalence among blacks for both AD and AD vascular risks of diabetes and hypertension when compared to whites. Research on cognitive aging has traditionally focused on how decline in various cortical and hippocampal (Hip) regions influences cognition. However, tau pathology emerges decades before amyloid pathology, appearing first in the brainstem (BS); particularly in the locus coeruleus (LC), the source of brain’s norepinephrine (NE). Our decade‐long studies in humans using a norepinephrine transporter (NET)‐selective radiotracer ([11C]MRB) have demonstrated a special vulnerability of LC to aging and stress.

Method

Co‐registration of PET (dynamic [11C]MRB), MRI and the FreeSurfer (FS) atlas images of each individual was used to generate regional time‐activity curves using Firevoxel. Binding potential (BPND) values were determined using MRTM2 with occipital as the reference region. Annual percent change (APC) of BPND was calculated based on linear regression (APC = 100 × (em
– 1), m: slope) and effects of age, gender and ethnicity on tracer binding were evaluated.

Result

For all HC (N=31), with both genders and all races included, age‐sensitive decline of NET availability was observed; e.g., 0.3‐0.5%/yr for Hip, BS and olfactory. However, our data reveals that the decline rate of NET is much faster among blacks starting in the mid‐30s, particularly in black males; e.g., 2‐3%/yr vs. 0.14‐0.23%/yr in thalamus and brainstem for black males vs. white males (p<0.00001).

Conclusion

In addition to our previously determined age effect on MRB‐NET binding, this report further reveals the role of ethnicity effects on NET availability. Our study showed that a faster decline of LC‐NE function occurs in blacks, possibly caused by cumulative stress to socioeconomic disadvantage and racial discrimination, and may be responsible for the different disease expression among blacks. Thus, NET availability imaging represents a novel biomarker approach to racial‐dependent strategies for diagnosis and assessment of therapeutic interventions.
Transition to dementia in people with late‐life depression compared to older people with other mental illnesses
Authors: Reppermund Simone , Heintze Theresa , Srasuebkul Preeyaporn , Trollor Julian N
Published: December 2021

Background

Depression is highly prevalent in dementia and has been reported as a risk factor for dementia. Given the growth of the older population and a potential link between depression and dementia, it is important to understand the health profiles and related service use, especially for possible treatment and prevention strategies. The objectives of this study were to examine the transition to dementia and to compare the health and service use profiles in people with late‐life depression and older people with other mental illness and.

Method

A retrospective population‐based study using 13 years of linked health data including 55,717 people aged 65 or older hospitalised with depression and 104,068 people aged 65 or older hospitalised with other mental illness. Logistic regression and cox proportional hazard models were used to analyse the risk of dementia.

Result

The most prominent differences between the two groups were the rates of delirium and self‐harm with a six times lower rate of delirium in people with late‐life depression and an eight times higher rate of self‐harm compared to those with other mental illness. Inpatients with late‐life depression had an increased risk of subsequent dementia by 12% compared to inpatients with other mental illnesses. Besides late‐life depression, only two other conditions, diabetes and cerebrovascular accidents, were associated with an increased risk for dementia.

Conclusion

Inpatients with late‐life depression have an increased risk of dementia compared to older inpatients with other mental illness. Our findings highlight the importance of clinical management and prevention of self‐harm and delirium. The growing ageing population, along with the high prevalence of mental illness and comorbidities in older adults, has significant implications for the planning and equipping of health services to meet the needs of affected individuals.
Association of ergothioneine with neurodegeneration and cerebrovascular disease in cognitive impairment and dementia
Authors: Wu Liu‐Yun , Cheah Irwin K. , Chong Joyce R. , Chai Yuek Ling , Hilal Saima , Chen Christopher , Halliwell Barry , Lai Mitchell Kim Peng
Published: December 2021

Background

Ergothioneine (ET) is a dietary amino‐thione with strong antioxidant properties and therapeutic potential for neurodegenerative and vascular diseases (Halliwell et al., 2018; Smith et al., 2020). Decreased blood concentrations of ET have been found in patients with mild cognitive impairment (Cheah et al., 2016), but its status in neurodegenerative and vascular dementias are currently unclear. We thus investigated the association of plasma ET levels with (1) cognitive impairment and dementia, (2) cerebrovascular disease (CeVD), namely white matter hyperintensities (WMH), cortical infarcts and lacunes and (3) brain atrophy.

Method

A cross‐sectional study was conducted in a total of 496 participants in an ongoing longitudinal study, including 88 subjects with no cognitive impairment (NCI), 201 subjects with cognitive impairment but no dementia (CIND), 207 dementia patients of whom 160 had Alzheimer’s Disease and 47 vascular dementia (VaD). All subjects underwent collection of blood samples, neuropsychological assessment, and neuroimaging. Plasma ET levels were measured with a high sensitivity liquid chromatography tandem‐mass spectrometry (LC‐MS/MS) method.

Result

Plasma ET concentrations were lowest in dementia (p<0.001 vs. NCI and CIND), with intermediate levels in CIND (p<0.001 vs. NCI). In multivariate analyses, lower levels of ET were significantly associated with CIND (OR, 0.20; 95% CI, 0.07–0.56; p<0.01) and dementia (OR, 0.06; 95% CI, 0.02–0.20; p<0.001) after adjustment for demographics and risk factors. There was a positive correlation between plasma ET and MMSE scores (r=0.341, p<0.001). Lower ET levels were also strongly associated with WMH (OR, 0.44; 95% CI, 0.123–0.85); p<0.01) and brain atrophy markers (cortical atrophy: OR, 0.42; 95% CI, 0.20–0.92; central atrophy: OR, 0.46; 95% CI, 0.22–0.93; medial temporal atrophy: OR, 0.45; 95% CI, 0.24–0.99, p<0.05 for all).

Conclusion

The incremental decreases in ET levels along the clinical continuum suggest that ET may be associated with disease severity and is a potential biomarker for early detection of cognitive impairment. Deficiency of ET may contribute towards neurodegeneration‐ and CeVD‐associated cognitive impairments by exacerbating the deleterious effects of oxidative stress in these conditions.
Person‐centred dementia care in an acute hospital: Experiences from nurses working in a specialized dementia unit
Authors: Cheong Chin Yee , TAY Felicia Hui En , Yap Philip Lin Kiat
Published: December 2021

Objectives

Person‐centred care (PCC) is synonymous with best practice in the care of persons with dementia (PWD). However, the focus has been in long‐term care settings with less attention in acute hospitals. We aimed to study the implementation of PCC in an acute hospital dementia unit (Care for Acute Mentally Infirm Elders [CAMIE]) from the perspectives and experiences of nurses working with PWD.

Method

This was an exploratory qualitative study involving individual, face‐to‐face, semi‐structured in‐depth interviews. A purposive sample of ten nurses participated in the interview. We employed an inductive thematic analysis approach to analyze the qualitative result.

Results

The findings highlighted the challenges e.g. managing challenging behaviour and the positive experiences e.g. meaningful connection with patients in providing PCC. The initial challenges were due to a lack of prior knowledge and experience. Through formal and informal learning, the nurses built confidence and competence, and also provided support to each other. They emphasized the importance of teamwork and camaraderie in the CAMIE team but raised concerns about the negative perceptions of non‐CAMIE nurses on the value of their work.

Conclusion

Despite the challenges, with adequate knowledge and robust organizational level support to embrace PCC as the care ethos, implementing of PCC is feasible among nurses in the acute care setting.
Inflammation biomarkers for future development of all‐cause dementia, Alzheimer's disease, and vascular dementia
Authors: Trares Kira , Schöttker Ben
Published: December 2021

Background

Inflammation is one of the key mechanisms involved in the development and progression of dementia. However, not all details on the association between inflammation and dementia have been explored yet. Inflammatory biomarkers can be measured at an early stage of dementia and thus can contribute to an early diagnosis. Besides, these biomarkers could contribute to drug development or therapeutic strategies.

Method

Biomarkers from the Olink Proseek® Inflammation panel were analyzed in blood samples of a longitudinal German, population‐based cohort including 1782 older adults. Logistic regression models were used to identify associations of these biomarkers with all‐cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) incidence. Strongly associated biomarkers were further analyzed in subgroup and sensitivity analyses for dementia risk factors like age, diabetes, and APOE ε4 polymorphism. Moreover, clusters including highly correlated biomarkers (r > 0.5) were built based on these biomarkers.

Result

During 17 years of follow‐up, 504 participants were diagnosed with dementia, including 163 AD and 195 VD cases. A total number of 56 biomarkers showed a significant association with all‐cause dementia, 22 biomarkers were significantly associated with AD, and 33 with VD incidence, even after correction for multiple testing. The strongest, independent associations were found for the biomarkers CX3CL1 (OR [95% CI] per 1 standard deviation (SD): 1.41 [1.24‐1.60]) and EN‐RAGE (1.41 [1.25‐1.60]) with all‐cause dementia incidence, EN‐RAGE (1.51 [1.25‐1.83]) and LAP TGF‐beta‐1 (1.46 [1.21‐1.76]) with AD incidence, and VEGF‐A (1.43 [1.20‐1.70]) with VD incidence.

Conclusion

This study was the first to assess the associations of blood‐based biomarkers from the Olink Proseek® Inflammation panel with all‐cause dementia, AD, and VD incidence in a large, prospective, population‐based cohort study. The biomarkers CX3CL1, EN‐RAGE, LAP TGF‐beta‐1, and VEGF‐A, were independently associated with different forms of dementia and have great potential as predictive biomarkers.
Development of 1,2,3,4‐tetrahydrocarbazole derivatives as dual binding cholinestarse inhibitors
Authors: Singh Manjinder , Sharma Pratibha , Arora Sandeep
Published: December 2021

Background

Acetylcholinesterase (AChE) is one of the most promising targets for treatment of Alzheimer’s disease. The 1,2,3,4‐tetrahydrocarbazole compounds have been reported to inhibit AChE, reduce plaque formation in AD. Hence our focus is on the synthesis and biological assesment of 1,2,3,4‐tetrahydrocarbazole derivative to manage Alzheimer’s disease.

Method

A total of 16, 1,2,3,4‐tetrahydrocarbazole derivatives were synthesized and assesed for AChE and BuChE (butyrylcholinesterase) inhibitory effect. After that, the protein‐ligand interactions and pharmacokinetic of most active derivatives were determined using in silico approaches.

Result

The in vitro assays showed that all 1,2,3,4‐tetrahydrocarbazole derivatives inhibited AChE and BuChE. Additionally, the in silico investigations exhibited that the designed derivatives have capability to intearct with both PAS (peripheral anionic) and CAS (catalytic active) sites of chomiesterase enzyme. The pharmacokinetic parameters prediction disclosed that all synthesized compounds have drug like properties.

Conclusion

The study revealed that the newly synthesized 1,2,3,4‐tetrahydrocarbazole ligands could be developed as cognitive enhancers and may be employed in cognitive disorders including Alzheimer’s disease. Thus, 1,2,3,4‐tetrahydrocarbazoles might be taken as lead for the management of Alzheimer’s disease.
Prognostic value of amyloid/tau/neurodegeneration (ATN) classification based on diagnostic cerebrospinal fluid samples for Alzheimer’s disease
Authors: Schaeverbeke Jolien , Delmotte Koen , Vandenberghe Rik , Poesen Koen
Published: December 2021

Background

As first objective, we examined in a clinical, real‐life setting, the prognostic value of cerebrospinal fluid (CSF) based Amyloid Tau Neurodegeneration (ATN) classification for subsequent cognitive decline during the three years following a lumbar puncture. The secondary objective was to investigate the prognostic value of CSF biomarkers as continuous variables.

Method

Retrospective data from an academic memory clinic sample of 228 patients (median age 67 (47‐85) years) were retrieved. CSF data (Innotest assays) were available in all patients and used for ATN classification: the cut‐off values were 798 pg/mL for amyloid‐beta 1‐42 (Aβ42) (A), 87 pg/mL for hyperphosphorylated tau (p181‐tau) (T), and 465 pg/mL for total tau (t‐tau) (N). A secondary analysis with ATN based on lower tau cut‐offs (p181‐tau: 58.9 pg/ml; t‐tau: 354 pg/ml) was also applied. Cognitive performance was evaluated by Mini Mental State Examination (MMSE) every 6 months over a period up to 36 months following the lumbar puncture. Linear mixed‐effects modelling was performed on non‐imputed data (minimum 3 MMSE scores) as well as on imputed data using the R packages ‘nlme’ and ‘mice’.

Result

In the current sample, classification showed 32.02% A‐/T‐/N‐, 33.33% A+/T‐/N‐, 17.11% A+/T+/N+, 11.84% A+/T‐/N+, 4.39% A‐/T‐/N+ and 1.32% A‐/T+/N+ (3 cases), with the A‐/T+/N‐ and A+/T+/N‐ class being absent. Hence the latter 3 classes were excluded from further analyses. The change of MMSE relative to A‐/T‐/N‐ over a 36 months period was significant in all four ATN classes: A+/T+/N+ = ‐4.78 points on the MMSE; A‐/T‐/N+ = ‐4.76; A+/T‐/N+ = ‐2.83; A+/T‐/N‐ = ‐1.96. The earliest significant difference in slope was seen in the A+/T+/N+ class at 12 months after baseline (Figure 1A). The effect of ATN class on future cognitive decline was confirmed for a different set of CSF thresholds (Figure 1B). All individual baseline CSF biomarkers including the Aβ42/t‐tau ratio showed a significant correlation with subsequent cognitive decline, with the highest correlation seen for Aβ42/t‐tau.

Conclusion

ATN classification based on CSF biomarkers has a statistically significant and clinically relevant prognostic value for the course of cognitive decline in a 3‐year period in a clinical practice setting.
Health conditions that predict Alzheimer’s disease and vascular dementia: A phenome‐disease association study
Authors: Beason‐Held Lori L , Kerley Cailey I , Chaganti Shikha , Moghekar Abhay , Thambisetty Madhav , Resnick Susan M , Landman Bennett A
Published: December 2021

Background

Poor health increases the risk of cognitive decline and dementia. Here, we examined medical records to determine health conditions that were most predictive of dementia at intervals prior to dementia diagnosis. This phenome‐disease association study (PheDAS) used ICD‐9 health code medical record data from participants in the Baltimore Longitudinal Study of Aging (BLSA).

Methods

Data were available for 347 Alzheimer’s disease (AD), 76 vascular dementia (VD), and 811 non‐demented control participants. Logistic regressions were performed associating ICD‐9 health codes with dementia status at 5 and 1 year(s) prior to dementia diagnosis and at the year of diagnosis, controlling for maximum age, sex and follow‐up length of medical record.

Results

In AD, the earliest and most consistent predictors across all time points included depression, erectile dysfunction, gait abnormalities, hearing loss, and nervous and musculoskeletal symptoms. Cardiomegaly, disorders of esophageal motility and non‐epithelial skin cancer were not significant until 1 year before dementia diagnosis. In VD, the earliest and most consistent predictors across all time points included abnormal EKG, cardiac dysrhythmias, cerebrovascular disease, non‐epithelial skin cancer, depression, and hearing loss. Atrial fibrillation, occlusion of cerebral arteries, and abnormal reflexes were not significant until 1 year before dementia diagnosis.

Conclusions

These findings suggest that some health predictors of future dementia begin at least 5 years before dementia diagnosis and are consistently seen over time, while others only reach significance closer to the date of diagnosis. These results also show that there are both shared and distinctive health predictors for AD and VD. Together, this study reinforces the need for proper care and treatment of modifiable health risk factors throughout the lifespan. This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.
Occupational complexity and neuroimaging measures of structural MRI and PET‐amyloid in a randomized controlled trial: FINGER
Authors: Rydström Anders , Stephen Ruth , Kåreholt Ingemar , Darin‐Mattsson Alexander , Liu Yawu , Ngandu Tiia , Rinne Juha O , Kemppainen Nina , Antikainen Riitta L , Bäckman Lars , Sindi Shireen , Soininen Hilkka , Strandberg Timo , Tuomilehto Jaakko , Kivipelto Miia , Solomon Alina , Mangialasche Francesca
Published: December 2021

Background

Higher occupational complexity has been associated with better cognition in late life, but associations with brain changes remain unclear. We assessedwhether occupational complexity was associated with baseline brain structural MRI measures and PIB‐PET amyloid burden in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER).

Method

FINGER is a two‐year, population‐based, multicenter, multidomain randomized controlled trial. Inclusion criteria included age 60‐77 years; Cardiovascular Risk Factors, Aging and Dementia Risk Score of at least 6; cognition at a mean level or slightly lower than expected for age. Participants (n=1260) were randomly assigned in a 1:1 ratio to a multidomain intervention group (diet, exercise, cognitive training, vascular risk management) or a group receiving general health advice. Primary outcome was change in cognition (Neuropsychological Test Battery). Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. The MRI analyses included a subgroup of 126 participants from three different FINGER study sites and the PiB‐PET measures included 42 participants from one study site. MRI regional cortical thickness and volumes were measured using the Freesurfer image analysis suite (version 5.0.3). Linear, logistic, and ordinal logistic regression models were used to assess the association between occupational complexity and neuroimaging measures, adjusting for age, sex, education, intracranial volume, and study site. Neuroimaging assessments included hippocampal and total gray matter volume, Alzheimer´s disease signature thickness, visually rated medial temporal atrophy (MTA), and amyloid accumulation.

Result

There was no association between occupational complexity and brain cortical thickness, volume measures, or PiB‐PET measures.

Conclusion

No association between occupational complexity and brain structure and amyloid burden was found in older adults at increased risk of dementia. These findings should be verified in larger cohorts.
Association between sleep, depressive symptoms, and pain with physical activity and physical functioning in the oldest old: CAIDE 85+ study
Authors: Kekkonen Eija , Hall Anette , Kulmala Jenni , Lisko Inna , Ngandu Tiia , Barbera Mariagnese , Hallikainen Merja , Soininen Hilkka , Kivipelto Miia , Solomon Alina
Published: December 2021

Background

The aim was to investigate 1) the associations of sleep, depressive symptoms, and pain with physical activity and physical functioning in the oldest old age group (85 years and older); 2) the effects of Covid‐19 related restrictions on physical activity in the oldest old.

Method

The data is from Cardiovascular Risk Factors, Aging and Dementia (CAIDE 85+) longitudinal cohort study in Eastern Finland. From the original cohort, participants were invited to follow‐up visit during 2019‐2020. Self‐reported measures were physical activity (active: ≥2 times a week/inactive: <2 times a week), sleep duration (hours/night). We also assessed depressive symptoms (BDI‐21 scale), sleep quality (PSQI), pain (RAND‐36), physical functioning (Short Physical Performance Battery (SPPB)) and Clinical Dementia Rating (CDR). Cross‐sectional associations of sleep quality and duration, depressive symptoms, and pain with physical activity and physical functioning were assessed using logistic regression, adjusted for age, sex, education and CDR.

Result

Altogether 194 individuals participated in the CAIDE 85+ study. The mean age was 88 (SD 4.5) years, and 90% (n=170) were community‐dwellers, and 66% (n=124) were physically active. Participants with long sleep duration (<8 hours/night) were less likely to be physically active (OR 0.10, 95% CI 0.03–0.40) compared to participants with normal sleep duration (6‐8 hours/night). Also, participants with pronounced pain (3rd tertile of RAND‐36 pain score) were also less likely to be physically active (OR 0.33, 95% CI 0.12–0.90) compared to the group with lowest level of pain. Participants with elevated depressive symptoms (BDI‐21 score ≥10) were more likely to have lower level of physical functioning (SPPB score ≤6), (OR 0.32 95% CI 0.12–0.84), compared to participants with no depressive symptoms. The results were similar when participants with CDR score ≥1 were not included in the analysis. Furthermore, of the 96 participants who answered questions about Covid‐19 related restrictions, 47% (n=38) reported no effects on physical activity, and 36% (n=29) reported physical activity level was decreased.

Conclusion

These preliminary results suggest that long sleep duration and pronounced pain are associated with physical inactivity. However, only elevated depressive symptoms are associated with low levels of physical functioning in the oldest old.
The role of biomarkers in cell counting with U‐Net CNN
Authors: Miramontes Silvia , Piergies Antonia M. H. , Grinberg Lea T. , Ushizima Daniela
Published: December 2021

Background

Imaging methods that are non‐destructive preserve tissue integrity and lead to improved topography analysis for the study of neurodegenerative diseases like Alzheimer’s Disease (AD). Immunofluorescence (IF) staining methods facilitate such investigations by addressing a gradient of intensity variations relevant for in situ cell detection [1] and morphology quantification. This paper reports on the colocalization of proteins and cell structures from human post‐mortem tissue by evaluating IF expression by means of TBR1 and NeuN biomarkers. We compare different U‐Net‐based models by exploring image representations obtained by combining image channels with different biomarkers.

Method

From an image dataset with 21 full‐size IF micrographs, we augment it by creating a cropping mechanism resulting in 40 to 60 image crops from each micrograph, each crop with 128x128 pixels. Later, we enhance the resulting 1,200 cropped images, and construct 3‐channel (x,y,z) image inputs of dimensions 128x128x3 for the U‐Net model in a two‐fold process: (I) stack all 3 channels with single‐channel IF cropped images corresponding to NeuN biomarkers (NeuN, NeuN, NeuN); (II) stack the single channel images of TBR1, NeuN, and a single image representing the maximum pixel intensities from TBR1 and NeuN images (TBR1, NeuN, max (TBR1, NeuN)). With a test‐train split of 70% ‐ 30%, and parameter tuning, we compare the two models via metrics such as neuron areas, counts, accuracy and recall.

Result

The model trained with channel stacking (II) outperforms the model trained with (I) with an accuracy and recall of 0.96 and 0.5, as opposed to 0.95 and 0.4. We also found a great variation in neuron area and counts as depicted in the images below.

Conclusion

While this is the first step in accelerating the quantification of neurons for the pathophysiology studies necessary for drug development, there is a need in establishing protocols for the generation of datasets with manual segmentation to further train our models. The inclusion of prior information about the expected neuron morphology increases the performance of our networks, and successfully deploy a foreseen automated pipeline. Reference: [1] Ehrenberg et al. A manual multiplex immunofluorescence method for investigating neurodegenerative diseases. Journal of Neuroscience Methods, June, 2020.
Midlife measures of lipid fractions and fasting glucose are associated with late‐onset Alzheimer disease
Authors: Zhang Xiaoling , Tong Tong , Chang Andrew , Ang Ting Fang Alvin , Tao Qiushan , Auerbach Sandford H. , Devine Sherral , Qiu Wendy , Mez Jesse , Massaro Joseph , Lunetta Kathryn L. , Au Rhoda , Farrer Lindsay A.
Published: December 2021

Background

Measures of cardiovascular and metabolic disease are well‐established risk factors for late‐onset Alzheimer disease (AD). However, it is poorly understood whether exposure to these risk factors in early adulthood is associated with AD in late‐life.

Method

Association of incident AD occurring after age 60 with measures of lipid fractions, hypertension, diabetes, blood glucose, BMI and smoking obtained prospectively across nine quadrennial examinations was evaluated in the Framingham Heart Study (FHS) Offspring cohort (n=5,124) using Cox proportional hazard models. Age‐ and sex‐adjusted models were tested for each risk factor measured at each exam and within three age groups (early adulthood=35‐50, middle adulthood=51‐60, late adulthood=61‐70). Additional models included covariates for risk factor‐specific treatment and APOE ε4 carrier status.

Result

During a mean follow‐up period of 31.7±6.7 years, a diagnosis of incident AD was established for 271 participants. A 15 mg/dL increase in high‐density lipoprotein cholesterol (HDL‐C) measured during early adulthood and middle adulthood was associated with a 19.1% decreased risk of AD in each group (HR=0.81 [95%CI 0.70, 0.96], P=0.011 and HR=0.81 [0.67, 0.97], P=0.019, respectively). An increased risk of AD was also associated with 15 mg/dL increases of triglyceride (TG) (HR=1.05 [1.002, 1.10], P=0.023) and low‐density lipoprotein cholesterol (LDL‐C) (HR=1.06 [1.003, 1.12], P=0.041) measured in early adulthood. A 15 mg/dL increase in fasting blood glucose (FBG) measured during middle adulthood was associated with a 11.0% increased risk of AD (HR=1.11 [1.03, 1.20], P=0.0039). These findings remained significant after adjusting for treatment. Survival analysis showed that AD risk was significantly higher and occurred earlier among individuals with FBG in the pre‐diabetic (100‐126 mg/dL) and diabetic (>126 mg/dL) ranges compared to those with normal FBG (<100 mg/dL) in middle adulthood (P=0.038), but not in late adulthood.

Conclusion

HDL‐C, LDL‐C, TG and FBG levels measured in cognitively normal individuals between ages 35 and 60 years are significantly associated with incident AD several decades later. Our findings suggest that careful management of cholesterol and glucose levels beginning in early adulthood can lower AD risk in later life including among APOE ε4 carriers, in addition to the benefits of promoting cardiovascular and metabolic health.
Relationships between well‐being and cognitive function among Native American, Black, and White participants in the Wisconsin Alzheimer's Disease Research Center
Authors: Wyman Mary F , Umucu Emre , Livingston Sydnee , Lambrou Nickolas H , Carter Fabu P , Van Hulle Carol A , Johnson Sterling C , Asthana Sanjay , Gleason Carey E , Zuelsdorff Megan
Published: December 2021

Background

High subjective well‐being is a hallmark of successful aging, and growing evidence demonstrates its associations with better cognitive function and slowed decline in aging adults. To date, predominantly white study cohorts preclude an understanding of well‐being as a protective factor in minoritized populations. Using validated NIH Toolbox Emotion Battery measures, we examined associations between three facets of psychological well‐being and cognitive test performance in a cognitively healthy cohort of Black, American Indian/Alaska Native (AI/AN), and white older adults enrolled in the Wisconsin Alzheimer’s Disease Research Center’s (ADRC) Clinical Core.

Methods

Participants with normal cognition and with complete Emotion Battery data for at least one visit were included in the analytic sample. Key well‐being predictors included t‐scores of self‐reported positive affect, general life satisfaction, and life meaning and purpose surveys. Outcomes of interest were performance on tests of processing speed and flexibility (Trails A and B completion time) and episodic memory (Rey Auditory and Verbal Learning Test, Trials 1‐5 & Delayed). The sample was stratified by race before cross‐sectional multivariable regression models were used to model demographic‐adjusted predictor‐outcome relationships.

Results

In the combined, predominantly female sample, average age was 63.8 (SD=8.3). AI/AN participants (N=25) were older, and Black (N=91) and AI/AN reported fewer years of formal education than their white peers (N=433; Table 1). No racial disparities were observed in positive affect or life purpose scores, but Black and AI/AN participants reported lower life satisfaction. Consistent relationships between life satisfaction and processing speed were observed: across all racial groups, higher t‐scores associated with faster completion time, though estimate precision was limited by small sample sizes (Table 2 and Figure 1).

Conclusions

These ADRC data reaffirm racial disparities in life satisfaction observed elsewhere, which is notable in light of the robust associations of life satisfaction with key components of executive function. Identifying modifiable sources of cognitive resilience and protection against age‐related change is crucial for addressing the dementia crisis and its burden on Black and Native communities. Our findings point to next steps including triangulation with AD biomarkers and exploring population‐specific upstream determinants of life satisfaction that can inform intervention efforts focused on well‐being.
Blood neurofilament light, Parkinson’s disease, Parkinsonism, and physical function in a longitudinal population study
Authors: Halloway Shannon , Desai Pankaja , Aggarwal Neelum T , Agarwal Puja , Evans Denis A , Rajan Kumar B
Published: December 2021

Background

Blood biomarkers of parkinsonism and Parkinson’s disease (PD) may allow for earlier identification of these conditions and improved longitudinal investigation of PD pathogenesis. Neurofilament light (Nf‐L), a neuronal cytoplasmic protein, is a biomarker of neurodegeneration measurable in CSF or blood. We examined the longitudinal association of serum Nf‐L with clinically diagnosed PD, parkinsonian signs, and physical functioning change over 16 years in a population‐based sample of Black and White older adults.

Methods

Data came from 1,327 older participants from the Chicago Health and Aging Project (CHAP), a longitudinal population‐based study of common chronic conditions of aging. Clinical evaluations included assessing parkinsonian signs in four domains, bradykinesia, parkinsonian gait, rigidity, and tremors using a structured version of the United Parkinson’s Disease Rating Scale. PD was diagnosed by board certified neurologists. Parkinsonian signs were reported as the four domain scores and a global parkinsonian score (combination of domain scores). Physical function was assessed by performance‐based tests. Serum Nf‐L was measured with an ultrasensitive immunoassay.

Results

After adjusting for demographic characteristics, the APOE‐e4 allele, and cognitive function, a 2‐fold higher concentration of serum Nf‐L was associated with the development of clinical PD (OR = 2.54, 95% CI: 1.70, 3.81), and global parkinsonian scores (OR = 2.44, 95% CI: 1.94, 2.94). This association was significant over five years before diagnosis. Compared to participants below 18.5 pg/mL of serum Nf‐L at baseline, participants in between 18.5–25.4 pg/mL, 25.4–37.3 pg/mL, and above 37.3 pg/mL had a higher odds ratio of clinical PD at all time intervals ranging from the time of diagnosis to greater than five years before diagnosis. A higher concentration of serum Nf‐L was associated with a faster decline in physical functioning over the duration of the study. In participants with 2‐fold higher concentrations of serum Nf‐L, the annual rate of decline in physical functioning increased by 0.15 units (95% CI: 0.21, 0.08).

Conclusions

Serum Nf‐L predicted the development of clinically diagnosed PD, parkinsonian signs, and physical functioning decline in a population‐based sample. Our findings suggest that Nf‐L may serve as a potential biomarker for physical functioning outcomes in older adults.