bluuebunny/crossref_metadata_2025 huggingface dataset:
Hourly, daily, weekly or monthly? Choosing the right data granularity for analysis of digital biomarker trajectories
Authors: Wakim Nicole I , Braun Thomas M , Kaye Jeffrey , Dodge Hiroko H
Published: December 2020

Background

The use of digital biomarker data provides the opportunity for frequent functional and cognitive assessments that were not previously available. Digital biomarker data are often collected in the form of time stamped data, which requires processing for interpretable applications in health care research. In general, time stamped data can be averaged, or condensed, into daily, weekly, or even monthly time intervals, which are referred to as time granularities. Data with fine time granularity can improve the fit of a model and increase signal strength, but it can also require more computational time and storage for analysis. There are no published guidelines explaining how to determine the best time granularity. We aim to provide a guideline to find a balance between computational efficiency and integrity of the data when analyzing longitudinal trajectories based on high frequency digital biomarker data in dementia research. We also provide a real‐world example to show how the guidelines can be applied.

Methods

There are four important factors of data that we need to investigate when determining appropriate granularity: (i) duration of follow‐up, (ii) variables of interest in analysis, (iii) pattern detection, and (iv) signal to noise ratio (SNR). Follow‐up time helps determine the highest reduction of time granularity that is feasible for the data. Variables of interest may only be available at certain time granularities. For pattern detection, clinical information about biological patterns will help determine time granularity. SNR uses variability in the data to determine how likely a signal will be detected during trajectory analysis.

Result

These factors are applied to an example involving walking speed derived from a longitudinal cohort study, the Intelligent Systems for Assessing Aging Change study (ISAAC). The data have been collected at the Oregon Center for Aging and Technology (ORCATECH) at the Oregon Health and Science University.

Conclusion

We highlighted common challenges researchers face when analyzing digital biomarkers and how we can use the guideline in selecting an appropriate time granularity before conducting analyses. The guideline will help improve scientific rigor in digital biomarker analyses.
Alterations of cortical thickness and gray‐white matter contrast in Alzheimer’s disease and Lewy body‐related cognitive impairment
Authors: Jeon Seun , Kim Hosung , Ye Byoung Seok , Evans Alan C.
Published: December 2020

Background

Gray and white matter alteration has been known in patients with neurodegenerative diseases including Alzheimer’s disease‐ (ADCI) and Lewy body‐related cognitive impairment (LBCI). We examined a distinct pattern of cortical thickness (CTH) and gray‐white matter contrast (GWC) alterations in these degenerative neurological diseases. Since the T1‐weighted MRI signal is closely related to myelin content, the GWC may reflect disease‐related alterations of myeloarchitecture along the cortical surface.

Methods

T1‐weighted MRIs were obtained from patients (demo‐matched, CDR‐SOB≤9) with ADCI (n=97), LBCI (n=93), and healthy controls (n=37). We measured CTH using the CIVET processing pipeline. GWC was calculated at each vertex as the difference between gray matter (sampled at 50% CTH) and white matter intensity (sampled at 1mm subcortical white matter), then this was normalized by their average. Group differences (controls vs. patients) and correlations (with neuropsychological scores) were examined using general linear models covarying for age, sex, education, intracranial volume, and several vascular risk factors. Results were corrected for multiple comparisons using random field theory p<0.05 (cluster‐forming threshold p=0.001).

Results

Patients with ADCI showed altered CTH in the brain regions typically affected in AD including the bilateral medial temporal, lateral temporo‐parietal, and posterior cingulate cortices. The pattern of GWC alteration was smaller and no change was shown in the lateral temporal lobe (Figure 1A). LBCI patients showed altered CTH in superior frontal, lateral temporal, basal frontal and occipital cortices. The GWC alteration pattern was shown in larger area, notably in the limbic and occipital cortices (Figure 1B). Memory function, in the AD‐spectrum, was more closely associated with CTH, while in the LB‐spectrum, it was more closely with GWC (Figure 2). Frontal/executive function has stronger association with CTH than with GWC in the AD‐spectrum, while the LB‐spectrum showed independent patterns of association in those measures (Figure 3). The visuospatial function was only associated with CTH in AD‐spectrum, and in LB‐spectrum, it was greater in CTH than in GWC (Figure 4).

Conclusions

We demonstrated distinct patterns of CTH and GWC alteration in ADCI and LBCI. Consideration of heterogeneous atrophy patterns may be important when planning prevention and treatment strategies, as they may have different responses to treatment in the disease progression.
Cerebrospinal fluid neuroinflammatory biomarkers along the Alzheimer disease continuum in Down syndrome
Authors: Carmona‐Iragui Maria , Iulita M. Florencia , Barroeta Isabel , Fernandez Susana , Altuna Miren , Videla Laura , Benejam Bessy , Valldeneu Sílvia , Muñoz Laia , Alcolea Daniel , Blesa Rafael , Lleó Alberto , Fortea Juan
Published: December 2020

Background

Alzheimer’s disease (AD) is the main medical problem and cause of death for adults with Down syndrome (DS). Glial activation is an early phenomenon central to AD pathophysiology; however, whether glial biomarker profiles in DS differ from sporadic AD remains unanswered. We compared cerebrospinal fluid (CSF) glial biomarkers along the AD continuum between DS individuals and sporadic AD cases and its relationship with CSF neurodegeneration biomarkers.

Method

Single‐center cross‐sectional study. We classified individuals with DS into three clinical subgroups: without cognitive impairment (aDS), prodromal AD (pDS) or with AD dementia (dDS). We determined CSF‐YKL40 and progranulin protein (PGRN) levels by ELISA (Quidel and Adipogen, respectively) and we compare them along the AD continuum in DS. For comparisons, we included subjects with sporadic prodromal AD (pAD) and AD dementia (ADd) and healthy controls. We studied correlations of YKL40 and PGRN with CSF‐total‐tau (Fujirebio‐Europe), phospho‐tau (Fujirebio‐Europe) and NfL (UmanDiagnostics) within participants with DS. We used Mann‐Whitney tests corrected for multiple comparisons and Spearman coefficients for correlations.

Result

Participants included were 56 aDS, 17 pDS, 27 dDS, 28 pAD, 55 ADd and 147 controls. YKL40 levels were lower in aDS compared to controls (p<0.0001) and along the AD continuum in DS compared to sporadic cases (pDS vs pAD, p= 0.0004 and dDS vs ADd, p=0.0002) (Figure 1a). Symptomatic AD was associated with an 88.8% increase in YKL40 levels in DS and with a 69.9% increase in sporadic AD. There were no differences in PGRN levels along the AD continuum in DS or between DS and sporadic AD; however, PGRN levels were lower in aDS than in HC (Figure 1b). Both YKL40 and PGRN levels positively correlated with total‐tau (r=0.3, p<0.001; r=0.4, p<0.001), phospho‐tau (r=0.87, p<0.001; r=0.41, p<0.001) and NfL, (r=0.82, p<0.001; r=0.43 p<0.001) levels in the group with DS.

Conclusion

CSF glial biomarkers in subjects with DS differ from that in healthy controls and sporadic AD. However, symptomatic AD is characterized by similar changes in astrocyte and microglial activation markers such as YKL‐40 and PGRN. Differences in the immune system and response to AD might have important therapeutic implications and deserve further research.
Novel ex vivo MRI atlas of the medial temporal lobe can be used to characterize structural changes due to Alzheimer’s disease pathology
Authors: Ravikumar Sadhana , Wisse Laura , Xie Long , Ittyerah Ranjit , Das Sandhitsu R. , Detre John A. , Grossman Murray , Lavery Madigan , Lim Sydney A. , Irwin David J. , Schuck Theresa , Trojanowski John Q. , Artacho‐Perula Emilio , Martin Maria Mercedes Iniguez de Onzono , Lee Eddie B. , Mizsei Gabor , Tisdall Dylan M. , del Mar Arroyo Jimenez Maria , Munoz Monica , Gonzalez Jose Carlos Delgado , Parada Marta Corcoles , de la Rosa Prieto Carlos , Sanchez Sandra Cebada , Prabhakaran Karthik , del Pilar Marcos Rabal Maria , Romero Francisco Javier Molina , Robinson John L. , Wolk David A. , Insausti Ricardo , Yushkevich Paul A.
Published: December 2020

Background

Finding effective biomarkers that can support early‐stage clinical trials is a major challenge in Alzheimer’s Disease (AD). MRI measures of structural change in the medial temporal lobe (MTL) have proven to be sensitive to change in the early stages of AD. However, other frequently comorbid non‐AD factors (e.g. cerebrovascular disease, TDP‐43 pathology) also cause changes in the MTL. For MRI biomarkers to detect changes specifically linked to AD pathology, patterns of structural change must be linked to the underlying neuropathology. To provide this linkage, we use ex vivo imaging with pathologically derived ratings of AD and non‐AD pathology to study the localized effects of the disease on MTL structure. We hypothesize that such an analysis can be used to define MTL “hotspots” where in vivo measures will be more sensitive to disease progression in preclinical AD than current state of the art biomarkers.

Method

Ex vivo MTL specimens from 24 donors were scanned at 0.2x0.2x0.2mm3 on 9.4T MRI. The specimens contain varying degrees of pathology spanning the spectrum of AD and common co‐morbid non‐AD pathologies. For 21 specimens, a pathologist provided semi‐quantitative ratings of tau and TDP‐43 severity (Table 1). Extending on techniques developed in our prior work, a computational atlas of the MTL was built via groupwise registration of all specimens’ MRI scans (Adler et al, 2018; Ravikumar et al, 2020). The atlas was used to investigate the correlation between tau pathology and cortical thickness.

Result

The developed atlas achieves excellent groupwise alignment and captures anatomical variability in the MTL despite its complex geometry (Figure 1). Correlation analysis between tau pathology and atrophy (correcting for age and TDP‐43) reveals significant clusters near the transentorhinal region and subiculum (Figure 2).

Conclusion

These correlation patterns are consistent with the early Braak stages and resemble results from a previous study which looked at the association between in vivo tau PET measures and atrophy (Das et al, 2019) (Figure 3). In future work, our novel ex vivo atlas will be leveraged to study variability in the distribution of tau pathology in 3D, by mapping quantitative serial pathology images into the atlas space (Figure 4).
Hypoconnectivity between locus coeruleus and medial temporal lobe during novelty predicts accelerated Aβ‐related cognitive decline
Authors: Engels Nina , Prokopiou Prokopis C. , Uquillas Federico d’Oleire , Scott Matthew R. , Schultz Aaron P. , Papp Kathryn V. , Farrell Michelle E. , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I.L.
Published: December 2020

Background

Tauopathy can be detected in the locus coeruleus (LC) decades before clinical symptoms or Aβ‐pathology. Following involvement of the LC, tau progresses to the medial temporal lobe (MTL), possibly via hyperactivity or connectivity. Given LC’s modulating role on brain function and its early involvement in proteinopathies that affect LC’s interaction with other brain regions, it is conceivable that individual variability in LC functional connectivity (FC) with the MTL will be related to Alzheimer’s disease (AD)‐related cognitive functioning. The LC plays an important role in novelty processing, learning and memory. Therefore, we aimed to examine whether LC‐MTL FC during novelty predicts Aβ‐related cognitive decline.

Method

All participants (N = 153; number of observations = 772; Figures 1,2) were clinically normal and part of the Harvard Aging Brain Study. Baseline PiB‐PET (cut‐off = 1.324 DVR), 3T‐fMRI data on a face‐name encoding task and longitudinal neuropsychological PACC5 data were obtained. The fMRI‐task instructed participants to remember face‐name pairs and stimuli consisted of novel and repeated faces. A dilated ex‐vivo validated LC‐template was registered to each individual using ANTs. SPM and ICA‐AROMA were used for motion and physiological artefact removal. An FDR‐corrected gPPI‐analysis (with age, sex, education covariates) established five regressors: novelty; repetition; LC BOLD‐activity; novelty x LC BOLD‐activity; repetition x LC BOLD‐activity. A linear contrast was created by subtracting the repetition interaction regressor from the novelty interaction regressor. LME models assessed whether the association between PACC5 and FC was dependent on PiB (linearly and quadratic), while correcting for age, sex, education and their interactions with time. Bonferroni correction was applied.

Result

The gPPI‐analysis demonstrated negative LC‐MTL FC during novelty versus repetition for every region of interest (p‐FDR<0.05; Figure 3), thereby indicating hypoconnectivity. The LME‐analysis revealed that hypoconnectivity of the LC‐Parahippocampal Gyrus predicted worse PACC5 performance, which accelerated at elevated PiB levels (p = 0.013; f = 0.11; Bonferroni‐adjusted; Figure 4). Similar results were apparent for LC‐hippocampus and LC‐amygdala FC.

Conclusion

This study demonstrates that the LC is less functionally connected with the MTL during novelty, and that this hypoconnectivity predicts Aβ‐related cognitive decline. This suggests that LC‐MTL hypoconnectivity might act as a marker of AD‐related processes. Future work will assess the relationship between LC FC and tau pathology.
Gait impairments on single and dual tasks in cerebral amyloid angiopathy
Authors: Sharma Breni , Gee Myrlene , Zwiers Angela , Sekhon Ramnik , Charlton Anna , Ismail Zahinoor , Camicioli Richard , Smith Eric E.
Published: December 2020

Background

Cerebral Amyloid Angiopathy (CAA) is a small vessel disease wherein amyloid beta protein is deposited in the vessels of the cerebral cortex and leptomeninges. Little is known about CAA and gait impairment, even though gait is known to be affected by Alzheimer’s disease (AD). We hypothesized that gait would be impaired in CAA compared to normal controls (NC), and that more complex mental tasks would elicit further impairments in AD compared to CAA.

Method

Participants were NC (n=44), non‐demented CAA (n=31), and mild AD‐dementia (n=16). The ProtoKinetics Walkway was used to capture footfalls over a 6 m walk during a single task (walking only) and two dual tasks of differing complexity (counting backwards by ones [simple task] and naming animals [complex task]). For gait velocity, the dual task cost was calculated as the percent change during dual task compared to preferred pace walking. Analysis of covariance was used to test group differences, controlling for age, sex, and height.

Result

CAA participants were older and more likely to be men (Table 1). Gait parameters during preferred pace walk, dual task with counting backwards, and dual task with animal naming are shown in Tables 2‐4. Across all three tasks, both CAA and AD performed poorer than NC on mean Stride Length, Stride Length variability, mean Stride Time, mean Velocity, and mean Cadence. However, mean Stride Width, and Stride Width variability did not differ. There were no differences between CAA and AD (Tables 2‐4). On measures of Velocity, the dual task cost for going from single task to counting backwards (simple dual task) was greater in AD than NC but not in CAA than NC (Table 5). The dual task cost for going from single task to naming animals (complex dual task) was greater in AD than CAA and NC.

Conclusion

Gait is impaired in CAA to a similar extent as in AD, however dual task cost was higher for AD possibly because of greater cognitive impairment. Future research should investigate causes of gait impairments in CAA, including the effects of hemorrhagic and ischemic lesions such as white matter hyperintensities.
Stakeholders' perception of the adoption potential of TAP: Lessons from Chile
Authors: Moraga Carolina , Gajardo Jean
Published: December 2020

Background

Chile’s National Plan of Dementia has been implemented since 2017. This national strategy has the urgent need to develop or adopt non pharmacological interventions targeting people with dementia and caregivers. The Tailored Activity Program (TAP) is an evidenced‐based program that has been translated to different contexts, however, its outreach in Chile is still under development. This study describes how key stakeholders involved in the National Plan of Dementia in Chile perceive this intervention’s characteristics.

Method

This is a qualitative study addressing the perceptions of key policy makers involved in the National Plan of Dementia on the characteristics of the TAP. Interviews were recorded and transcribed, and content analysis was used to describe stakeholders’ perception. Written consent was completed by all participants. Ethical approval was obtained from the Scientific Ethics Committee of Adults, Metropolitan Health Service, Santiago, 2019.

Result

Seven stakeholders were interviewed, all directly involved in the design, implementation, or evaluation of the actions part of the National Plan of Dementia in Chile. Six main categories describing stakeholders’ perception of TAP were produced: 1) Feelings towards TAP, 2) How they see TAP, 3) What to expect from TAP, 4) Institutional fit, 5) Profiles of providers, and 6) Suggestions for a pilot study.

Conclusion

Stakeholders in Chile show a positive perception of the TAP, offering relevant information on the potential adoption of the TAP in a new context.
Impairment in recall after contextual fear conditioning and activity dependent protein translation in ovariectomized Alzheimer’s disease mouse model
Authors: Kommaddi Reddy Peera , Diwakar Latha , Gowaikar Ruturaj , Karunakaran Smitha , Ravindranath Vijayalakshmi
Published: December 2020

Background

Female sex is one of the major risk factor for developing late‐onset Alzheimer’s disease (AD). Human studies have demonstrated that the prevalence of AD is higher in women compared with men. Although neuroprotective effect of estrogen is well recognized, the underlying pathogenic mechanisms explaining the higher burden of AD in women are unclear, taking into account the longer lifespan in women. Thus, we attempted to investigate the gender‐specific differences during the progression of the disease in an AD mouse model. We examined behavioural and activity dependent protein translation in female AD mice after ovariectomy and compared it with sham‐operated female mice of similar age in order to study the effect of female sex hormones in female AD mouse.

Methods

Wild type and APP/PS1 female mice underwent an ovariectomy and sham surgery. The cognitive task we used in AD mouse model is the recall following contextual fear‐conditioning (cFC). After ovariectomy and behavioural assessment we prepared synaptoneurosomes from hippocampus and performed 35S methionine incorporation assay without or with KCl stimulation.

Results

Female APP/PS1 mice did not show deficient recall upon cFC at 2, 4 and 6 months of age. However, female APP/PS1 mice showed deficient recall following cFC only after 8 months of age and this was sustained as mice aged further. Activity dependent synaptic protein translation was affected only at 8 months of age and no deficits were observed in 4 months old APP/PS1 female mice. In contrast, ovariectomized APP/PS1 mice displayed deficient recall upon cFC at 4 months of age and this recall deficits were sustained until 8 months of age as examined. Further, activity dependent protein translation was also impaired in 4 months old ovariectomized APP/PS1 mice compared with sham female APP/PS1 mice and this impairment was persistent until 8 months of age in these ovariectomized APP/PS1 mice.

Conclusions

Our results indicate that deficits in recall following cFC and loss of activity dependent protein translation occurred in female APP/PS1 mice only as they aged or if they were ovariectomized at younger age. Thus, estrogen plays a protective role even in the presence of relatively higher levels of β‐amyloid.
Synaptosomal actin interactome analysis in an Alzheimer’s disease mouse model
Authors: Kommaddi Reddy Peera , Verma Aditi , Chandran Mahesh , Jaleel Abdul , Ravindranath Vijayalakshmi
Published: December 2020

Background

Filamentous actin (F‐actin) is the major cytoskeleton protein present in dendritic spines and it is an essential element for defining dendritic spine structure. We have shown that synaptosomal F‐actin levels were significantly decreased in APP/PS1 mice as early as 1 month of age. Further, reduced form of F‐actin is diminished and glutathionylated F‐actin is significantly increased in synaptosomes of 1 month old APP/PS1 mice. Synaptic neurotransmission and synaptic plasticity are dependent on the dynamic regulation of the actin through actin‐interacting and actin‐modulating proteins. Recent studies highlight that F‐actin nanoarchitecture is susceptible to several key regulators such as reactive oxygen species, cofilin and drebrin that are present in the dendritic spines. Yet, how synaptosomal F‐actin organization is regulated remains poorly understood. To address this, we characterized actin interactome in synaptosomes prepared from wild type and APPSwe/PS1ΔE9 (APP/PS1) mice.

Methods

We utilized age matched wild type (WT) and APP/PS1 mice for our experiments. Synaptosomes and highly enriched F‐actin and G‐actin fractions from synaptosomes were isolated from WT and APP/PS1 mice. We performed immunoprecipitation using all these fractions with an anti‐actin polyclonal antibody and eluted in Laemmli sample buffer. The IP elutes were resolved using SDS‐PAGE gels, all proteins purified from gels, and analysed by LC‐MS/MS spectrometry.

Results

We detected approximately 620 synaptic proteins in synaptosomes from both wild type and APP/PS1 mice at the age of six months. About 110 proteins were upregulated and 198 proteins down regulated in synaptosomes of APP/PS1 mice. We identified 69 proteins that were associated with F‐actin in WT mice while only 26 proteins interacted with F‐actin in APP/PS1 mice in synaptosomal F‐actin fraction. Further, we detected G‐actin‐interaction only with 10 proteins in WT and 15 proteins in APP/PS1 mice in synaptosomal G‐actin fraction. However, we were able to identify 401 proteins in WT and 444 proteins with F/G‐actin‐association in synaptosomes of APP/PS1 mice compared with WT mice.

Conclusions

Our result defines a provisional synaptosomal actin interactome in mouse brain cortex of WT and APP/PS1 mice and identifies several critical regulator proteins that may be involved in the progression of AD pathogenesis.
Genetic (APOE, BDNF) influences on functional language network connectivity in healthy older adults
Authors: Pietzuch Manuela , Bindoff Aidan , Sforazzini Francesco , Vickers James C
Published: December 2020

Background

Language is a crucial function that is preserved in healthy ageing. Broca’s and Wernicke’s area are known to be parts of the language network associated with speech production and comprehension, respectively. Pathological alterations that are identified in Alzheimer’s disease (AD) can be assessed using resting‐state fMRI. In particular, levels of oxygen in blood flow is measured as a proxy marker of brain activity. Functional connectivity with the Broca’s and Wernicke’s areas may be potential biomarkers of early brain changes associated with AD‐related genes, such as APOE and BDNF. Therefore, the objective of this study was to investigate age‐related differences in functional connectivity in the language networks (Broca’s and Wernicke’s area) associated with BDNF Val66Met and APOE polymorphisms in cognitively healthy older persons (n = 76).

Method

Data was pre‐processed using FSL. First level MELODIC (motion correction, brain extraction, and high‐pass filtering (100)) was applied for each dataset using Independent Components Analysis (ICA). Seed‐based correlation analysis was performed to investigate functional connectivity between the regions of interest and the rest of the brain.

Result

There were no significant differences in functional connectivity between the seed regions and other regions for APOE or BDNF (adjusted for age), but in a model with APOE + BDNF, age was positively correlated with functional connectivity between left Broca’s area and left frontal gyrus p = .003, as well between Wernicke’s area and right putamen and right supramarginal gyrus p = 0.02. Significant interactions indicating stronger functional connectivity in Met/ε3 than Met/ε4, p = 0.007, in Met/ε3 than in Val/ε3, p < .0001, and in Val/ε3 than Val/ε4 carriers, p < .0001, between the language networks and various brain regions, such as pre‐ & postcentral gyrus, parahippocampal gyrus, and precuneus.

Conclusion

These finding suggest that the degree to which the language network is interconnected may be associated with genetic interactions in the absence of clinical signs of disease. Disconnections within the functional language network may contribute to the loss of speech and comprehension in Alzheimer’s disease.
Evolution of clinical‐pathological correlation of early‐onset Alzheimer's disease: 1994–2009 vs 2010–2017
Authors: Sarto Jordi , Mayà Gerard , Molina Laura , Balasa Mircea , Gelpi Ellen , Aldecoa Ivan , Borrego Sergi , Contador José , Ximelis Teresa , Guasp Mar , Archilla Iban , Sanchez‐Valle Raquel , Lladó Albert
Published: December 2020

Background

Early onset Alzheimer disease (EOAD) (age at onset < 65 years) represents an important cause of early‐onset dementia. EOAD has some clinical, pathologic and neuroimaging differences compared to the late onset form of the disease that makes this subset of patients more difficult to diagnose and manage. Our objectives are to describe the clinical‐pathological correlation of a cohort of pathology‐confirmed EOAD, and to compare the findings with our antecedent EOAD cohort.

Method

Clinical and neuropathological data of subjects from the Neurological Tissue Bank‐Hospital Clínic/IDIBAPS (Barcelona, Spain, 2010‐2017) with postmortem confirmation of AD and age of onset before 60 years were collected retrospectively and analyzed. Patients with PSEN1, PSEN2 and APP mutations or insufficient clinical data were excluded. The findings were compared with those of our previously reported EOAD cohort (n = 40, 1994‐2009).

Result

A total of 36 new patients (44% women) were included. The mean age at onset was 55 years (SD ± 3.5), the mean of diagnostic delay was 2.8 years (SD ± 1.8) and the mean duration of disease was 10.4 years (SD ± 4.2). An onset with typical/episodic memory impairment was observed in 83% of the subjects. There was a lack of clinico‐pathological correlation on initial and final clinical diagnosis in 11% and 8%, respectively. Initial misdiagnoses were frontotemporal dementia (n = 1) and non‐neurodegenerative causes (n = 3), while final misdiagnoses were dementia with Lewy bodies (n = 1), frontotemporal dementia (n = 1) and progressive supranuclear palsy (n = 1). Three patients underwent AD biomarker analysis (3 CSF, 1 amyloid PET), and were consistent with AD profile. The former cohort had less typical/amnestic presentations (χ2 = 4.1, p = 0.04), a trend towards higher percentage of misdiagnoses (23% on initial diagnosis and 20% on final diagnosis, p non‐significant) and a similar diagnostic delay (3.1 years). Neuropathology showed, in addition to AD‐pathology, cerebral amyloid angiopathy in 94% and Lewy‐body copathology in half of patients; these data was similar to the previous cohort.

Conclusion

There is a trend towards diagnostic improvement in EOAD, that might be explained by improved diagnostic criteria, increasing experience on EOAD, a higher number of typical presentations and the beginning of use of biomarkers, although diagnostic delay and neuropathological findings remain similar.
Associations of olfaction with mild cognitive impairment and cognitive function in older adults: A population‐based study
Authors: Dong Yi , Wang Yongxiang , Liu Keke , Hou Tingting , Ren Yifei , Cong Lin , Tang Shi , Zhang Qinghua , Qiu Chengxuan , Du Yifeng
Published: December 2020

Background

Olfactory function might be impaired in the early stage of the dementing process, and thus, olfactory test may be useful for identifying elderly persons at an increased risk. However, previous studies that investigate the relationship between olfactory function and cognitive phenotypes have been scarcely conducted among older people living in the rural communities and the associations of olfaction with specific cognitive remains unclear. We sought to examine the relationship of olfactory function with global cognitive ability and various domains of cognitive function among rural‐dwelling Chinese older adults.

Method

This population‐based cross‐sectional study included 3003 dementia‐free participants (age ≥65 years; 57.3% women; 37.7% illiterate) in the baseline examination (March‐September 2018) of the Multidomain Interventions to Delay Dementia and Disability in Rural China (MIND‐CHINA) study. The 16‐item Sniffin’ Sticks identification test (SSIT) was performed to assess olfactory function. Global cognitive function was evaluated with the Chinese version of the Mini‐Mental State Examination (MMSE) and a neuropsychological battery was used to assess memory, language, attention, and executive function. We followed the Petersen’s criteria to define mild cognitive impairment (MCI). Data were analysed with multiple logistic regression and the general linear regression models.

Result

Of the 3003 participants, MCI was defined in 335 persons (11.2%). Multiple logistic regression analysis suggested that SSIT score (range 0‐16) was associated with an odds ratio of 0.90 (95% CI 0.87‐0.93) for MCI. Multiple general linear regression analysis showed that SSIT score was significantly associated with the scores of MMSE test (β coefficient=0.07, 95% CI 0.03‐0.11), z‐score of memory (β coefficient=0.28, 95% CI 0.12‐0.45), language (β coefficient=0.35, 95% CI 0.17‐0.52), and attention (β coefficient=0.59, 95% CI 0.38‐0.78), but not with the z‐score of executive function (β coefficient=0.05, 95% CI ‐0.11‐0.22).

Conclusion

A greater olfactory identification ability is associated with a lower likelihood of MCI and better performances in global cognitive function, attention, memory, and language function, but not in executive function, among Chinese older adults who are living in the rural communities with limited education.
The effect of multimodal comprehensive care methodology training on oral health care professionals’ empathy for patients with dementia
Authors: Kobayashi Masaki , Ito Mio , Iwasa Yasuyuki , Motohashi Yoshiko , Edahiro Ayako , Shirobe Maki , Hirano Hirohiko , Honda Miwako
Published: December 2020

Background

The prevalence of oral diseases in people with dementia has increased, and such patients have worse oral health than do people without dementia. However, in the provision of oral care, they often exhibit care‐resistant behaviours. Empathy is an important element of health care professionals who provide dental care for people with dementia. A study was conducted to assess whether a multimodal comprehensive care methodology training programme is associated with an improvement in empathy for people with dementia among oral health care professionals.

Methods

This research was a pre‐post prospective study. A total of 45 dentists and dental hygienists participated in a 7‐hour multimodal comprehensive care methodology training programme. The empathy of the participants for their patients was evaluated by the Jefferson Scale of Physician Empathy‐Health Professionals Version (JSPE‐HP) before and one month after the training (primary outcome). Each participant listed 3 patients from his or her clinical practice about whom he or she felt that providing dental care to them was difficult due to dementia. The oral health of the 3 patients refusing care provided by each participant was evaluated by the Oral Health Assessment Tool (OHAT) before and one month after the training (secondary outcome).

Results

The post‐training response rates were 87% (21 dentists, 18 dental hygienists). Over the course of the programme, the multimodal comprehensive care methodology training significantly increased the empathy score from pre‐training to post‐training (from 113.97 to 122.95, P<0.05, effect size=0.9). Regardless of gender, profession and years of clinical experience, all post‐training subgroup scores were higher than the pre‐training subgroup scores. The oral health of patients, as assessed by the OHAT, was significantly improved compared with their oral health before the training (from 6.54 to 5.71, P<0.05).

Conclusions

Multimodal comprehensive care methodology training was associated with an improvement in oral health professionals’ empathy for patients with dementia and an improvement in the oral health of their patients.
The association between ambient air pollution and cognitive impairment in community‐dwelling older adults: Six‐year cohort study TIGER
Authors: Tsao Shu‐Ping , Chen Jen‐Hau , Yu Hwa‐Lung , Chiou Jeng‐Min , Chen Ta‐Fu , Lai Liang‐Chuan , Chen Yen‐Ching
Published: December 2020

Background

Ambient air pollution exposure has been related to cognitive impairment. Several studies have started to explore the association of particulate matter and nitrogen oxides with cognitive impairment, studies evaluated the effect of long‐term exposure to ozone(O3), carbon monoxide (CO) and sulfur dioxide (SO2) are sparse.

Method

This study is part of the ongoing Taiwan Initiative for Geriatric Epidemiological Research (TIGER). A total of 605 participants (Age 65+) were recruited from a teaching hospital in northern Taiwan in 2011 and followed up biennially. After exclusion and loss to follow‐up over 6 years, a total of 292 participants were included for analyses. Global cognition was assessed by Montreal Cognitive Assessment‐Taiwanese version; domain‐specific cognition (logical memory, attention, verbal fluency, and executive function) were assessed by a battery of neuropsychological tests. The data of three air pollutants (O3, CO and SO2) were obtained from 27 monitor stations of Taiwan Environmental Protection Administration (EPA) between 1993 and 2010. Air pollutants were tertiled into low, moderate, and high levels. Spatial‐Time Analysis Rendering with Bayesian Maximum Entropy was utilized to establish the spatial‐temporal model. Logistic regression model was utilized to assess the association of exposure to air pollutants and global or domain‐specific cognition over 6 years adjusting for important covariates.

Result

The 17‐year average level was 39.40ppb for 8‐hour O3, 1.47ppm for 8‐hour CO, and 4.70ppb for daily SO2, which were below the EPA standards. Exposure to high‐level O3 (>40.83 ppb) was associated with poor executive function [adjusted odds ratio (aOR)=2.14, 95% confidence interval (CI)=1.05‐4.35] compared with low‐level O3. No significant association was observed between O3 or CO and global cognition or other cognitive domains. SO2 were not associated with cognitive function over 6 years.

Conclusion

Long‐term (17 years) exposure to O3, CO and SO2 lower than the EPA standards showed significant association with cognitive domains in a 6‐year cohort of community‐dwelling older adults. Future revisions of air standards may need to consider epidemiologic studies exploring the relation between exposure to these air pollutants and cognitive impairment.
Relationship between sleep structure, memory and size of the hippocampus
Authors: Silhan David , Holla Marie , Dudysova Daniela , Evansova Katarina , Koprivova Jana , Miletinova Eva , Buskova Jitka , Bartos Ales
Published: December 2020

Background

Sleep is important for consolidating declarative memory. Hippocampus is considered an important structure in this process. Our goal was to assess relationship between sleep structure, memory and size of the hippocampus.

Method

18 patients (4 men, age range 60 ‐ 80 years) underwent polysomnography, neuropsychological examination and brain MRI (3 T). Sleep efficiency, percentages of REM and non‐REM sleep stages were calculated. Delayed recall score in Rey Auditory Verbal Learning Test (RAVLT) was used to assess memory. Size of the hippocampus was evaluated using MRI visual scale named Hip‐Hop (Hippocampal‐Horn percentage). Statistical analyzes were performed using Spearman´s Rank correlation coefficient.

Result

We found strongly positive correlation between sleep efficiency and RAVLT (r = 0,73, p < 0,001). There was also positive correlation between RAVLT and percentage of REM sleep (r = 0,49, p < 0,05), but correlation with percentages of non‐REM sleep stages was not significant. We found positive correlation between sleep efficiency and size of the hippocampus only in the left hemisphere (r = 0,55, p < 0,02). RAVLT was also positively correlated with size of the hippocampus only on the left (r = 0,58, p < 0,01). We did not find significant correlation between size of the hippocampus and percentages of REM neither non‐REM sleep stages.

Conclusion

Sleep efficiency and percentage of REM sleep seem to be important for memory. Sleep efficiency and memory reflect size of left hippocampus according to our results. Supported by grants PROGRES Q35, LO1611, MH CZ DRO 00023752, 260388/SVV/2018, NV18‐07‐00272 and NV19‐04‐00090.
Impact of baseline impaired sleep, depressive symptoms and pain on physical activity in the FINGER multidomain lifestyle trial
Authors: Pietilä Eija Kristiina , Hall Anette , Ngandu Tiia , Kivipelto Miia , Antikainen Riitta , Havulinna Satu , Kulmala Jenni , Laatikainen Tiina , Levälahti Esko , Paajanen Teemu , Soininen Hilkka , Strandberg Timo , Solomon Alina
Published: December 2020

Background

Physical inactivity is a major concern for public health. Physical activity (PA) is an important protective factor against Alzheimer’s disease and dementia. Therefore, possible barriers to PA, such as impaired sleep, depressive symptoms and pain may need to be considered in prevention programs. The study aim was to investigate whether impaired sleep, depressive symptoms and pain at baseline would impact PA after a 2‐year multidomain lifestyle intervention in individuals at‐risk of dementia.

Method

The data was from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) 2‐year randomized controlled trial in 1260 older individuals at‐risk of dementia. PA (active/inactive), sleep duration (hours/night), and sleep quality (composite index based on 6 questions) were self‐reported. Depressive symptoms were assessed using the Zung scale, and bodily pain using RAND‐36. Associations of impaired sleep, depressive symptoms, or pain at baseline with PA at baseline and at the 2‐year visit were assessed using binary logistic regression models, adjusted for randomization group, age, sex, education, marital status, and body mass index.

Result

At baseline, participants sleeping on average ≤6 hours per night (n=268, 21%) reported poorer sleep quality, more depressive symptoms, more pain, and were also less physically active than participants with longer sleep duration. Participants with more depressive symptoms were less likely to be physically active at baseline (OR=0.97, 95%CI 0.95‐0.99). The odds of being physically active at 2‐year visit were increased in the intervention group, compared to control group (OR=1.9, 95%CI 1.4‐2.7). Being physically active at baseline also increased the odds of being physically active at 2‐year visit, (OR=8.4, 95%CI 5.8‐11.2). Compared to normal sleep duration (between >6 and <9 hours per night) at baseline, short sleep duration (≤6 hours per night) reduced the odds of being physically active at the 2‐year visit (OR=0.5, 95%CI 0.4‐0.8).

Conclusion

These preliminary findings from FINGER trial suggest that especially impaired sleep may need to be considered in prevention programs. Due to the associations between sleep quality, sleep duration, depressive symptoms and pain, further investigation is highly needed.
Correlations of plasma kynurenines with CSF levels, and their relation to markers of Alzheimer’s disease pathology, diagnostic phases and cognitive performance
Authors: Bakker Lieke , Koehler Sebastian , Choe Kyonghwan , van den Hove Daniel L.A. , Kenis Gunter , Eussen Simone J.P.M. , Ueland Per M. , Verhey Frans R.J. , Ramakers Inez H.G.B.
Published: December 2020

Background

Finding novel biomarkers for Alzheimer’s disease (AD) for prediction, diagnosis or disease monitoring is a key research area. The kynurenine pathway(KP) consists of different metabolites of the essential amino acid tryptophan that have putative neurotoxic and ‐protective properties such as NMDA‐receptor agonism or potent antioxidation. Small clinical studies have shown altered levels in blood plasma and cerebrospinal fluid(CSF) in AD and other neurodegenerative diseases. However, whether peripheral kynurenine concentrations in plasma resemble those found in CSF is still largely unknown. The present study aims to investigate whether kynurenine concentrations in plasma correlate with those measured in CSF, and to study the role of kynurenines as biomarkers for AD.

Method

This study uses baseline data from 800 participants obtained in the Biobank Alzheimer Centrum Limburg(BBACL) study, an ongoing prospective cohort study in patients of the memory clinic of the Maastricht University Medical Center, the Netherlands. Blood plasma and CSF concentrations (CSF available for 151 participants) of tryptophan, kynurenine, kynurenic acid, 3‐hydroxykynurenine, xanthurenic acid, anthranilic acid, 3‐hydroxy anthranilic acid, quinolinic acid and picolinic acid were determined by means of liquid chromatography‐tandem mass spectrometry. Additionally, Ab1‐42, total‐tau and phosphorylated tau in CSF were determined using commercially available single‐parameter ELISA methods. Correlational and multiple linear regression analyses studied associations between plasma and CSF kynurenine levels, associations of CSF kynurenine concentrations with AD pathological markers, differences in plasma and CSF kynurenine levels in different diagnostic phases (subjective cognitive decline, mild cognitive impairment, dementia) and their associations with cognitive performance.

Result

Plasma concentrations of tryptophan (r = .43, p <0.001) and KP metabolites kynurenine (r = .42, p <0.001), 3‐hydroxykynurenine (r = .37, p <0.001), kynurenic acid (r = .32, p <0.001), anthranilic acid (r = .59, p <0.001), quinolinic acid (r = .67, p <0.001) and picolinic acid (r = .76, p <0.001) significantly correlated moderately to high with their corresponding CSF concentrations. Associations with Ab1‐42, t‐tau and p‐tau, disease stages and neuropsychological test scores are currently being analyzed and will be presented.

Conclusion

From a diagnostic viewpoint these results are promising, as the collection of plasma samples is less invasive compared to CSF.
Agreement between FDG‐PET and CSF biomarkers for AD
Authors: Rodrigo‐Herrero Silvia , Garcia‐Solis David , Sanchez‐Arjona Maria Bernal , Franco‐Macías Emilio
Published: December 2020

Background

NICE 2018 guidelines recommend additional tests for the diagnosis of Alzheimer's disease (AD): FDG‐PET, or CSF biomarkers (T‐tau, P‐tau, Abeta42, Abeta40). If we cannot establish the diagnosis after one of the two tests, we should consider the other one. The objective is to study the agreement between FDG‐PET and CSF for diagnosing AD pathology in Mild Cognitive Impairment (MCI) or Mild Dementia stage (Global Dementia Scale 3‐4).

Method

We conducted a retrospective analysis of patients from July 2017 to May 2019 at the University Hospital Virgen del Rocio (Southern area of Spain, Andalusia). All patients were diagnosed with MCI (GDS‐3) or Mild Dementia (GDS‐4). We performed a CSF study ( Abeta42, T‐tau, P‐tau, and ratios; ELISA or automated method‐Elecsys‐) and FDG‐PET (blind to CSF results). We reviewed CSF trough the Biobank database ("Alzheimer's and other dementias") and FDG‐PET results from clinical database Histories. We classified CSF results as "positive CSF‐AD," or "negative CSF‐AD," following recommended cut‐off points. The classification of FDG‐PET was as well positive or negative, according to the presence or absence of typical AD hypometabolism. We studied the agreement between CSF and FDG‐PET with contingency tables and the Kappa index.

Result

We included 58 cases in the analysis. The mean age was 65.93 ± 8.38 years (range 51‐82); 31 (53.4%) females, 27 (46.6%) males. The average score in MMSE was 21.36 ± 4.68. The agreement was high‐grade (Kappa index = 0.60). 35 out of 39 cases with "positive CSF AD" had "positive FDG‐PET." 13 out of 19 cases with "negative CSF AD" had "negative FDG‐PET." There was disagreement in 10 cases, possibly due to false‐negative CSF, false‐positive FDG‐PET, or false‐negative FDG PET.

Conclusion

Despite not being a biomarker of the pathophysiology of AD, PET FDG has a diagnostic recommendation (NICE Guidelines 2018; Andriuta et al. J Alzheimers Dis. 2016). In this study, concordance with biomarkers in CSF was high‐rated, as shown in previous studies (Rubi S. et al. Rev Esp Med Nucl Imagen 2018). However, in 10 of the 58 cases, we had disagreements, supporting the recommendation to perform both CSF and FDG‐PET in doubt diagnoses.